Clinical trial NCT04106557
Conditions: Primary Disease or Condition Being Studied: Angelman Syndrome (AS)
Sponsor: Healx AI
Start date: 2019-09-09; Completion date: 2020-11-02
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of oral OV101 (gaboxadol) in pediatric subjects with Angelman syndrome.

Detailed description:

Arms: arm 1: OV101 (gaboxadol), oral, provided once daily at bedtime for 12 week duration arm 2: Matching placebo,oral, provided once daily at bedtime for 12 week duration
Interventions: intervention 1: Gaboxadol intervention 2: Placebo
Intervention descriptions: intervention 1: OV101 versus placebo once daily at bedtime for 12 weeks intervention 2: Matching placebo capsules to OV101 capsules.

Protocol documents:
Prot_000.pdf: 
Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
IND 129,003
EUDRA-CT 2019-002907-17
CLINICAL STUDY PROTOCOL 
 
A MulticeNter, Randomized, Double-Blind, Placebo-Controlled, Parallel- 
Group, Phase 3 Study to Evaluate the Efficacy and Safety of OV101 in 
PediaTric IndividUals With AngelmaN SyndromE (NEPTUNE) 
PROTOCOL NUMBER OV101-19-001 
Sponsor:
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
Sponsor Contact: 
Mathews Adera, MD 
Vice President, Clinical Development 
Telephone: 570-620-6290 
 
 
Medical Monitor: 
Eric J Christopher, MD, FAPA 
Associate Medical Director; PPD 
Eric.Christopher@ppdi.com 
 
Date of Amendment 5: 
 
26 January 2021 (Version 6.0)  
Date of Amendment 4: 
27 June 2020 (Version 5.0) 
Date of Amendment 3: 
19 June 2020 (Version 4.0) 
Date of Amendment 2: 
18 April 2020 (Version 3.0) 
Date of Amendment 1: 
31 January 2020 (Version 2.0) 
Date of Original Protocol: 
30 May 2019 (Version 1.0) 
 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Ovid Therapeutics Inc.
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of Ovid Therapeutics Inc. The study will be conducted according to the 
International Council for Harmonisation harmonised tripartite guideline E6 (R2): Good 
Clinical Practice. 
Eric J Christopher, MD, FAPA
Associate Medical Director; PPD 
Eric.Christopher@ppdi.com 
Mathews Adera, MD
Vice President, Clinical Development 
Telephone: 570-620-6290


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Mathews Adera, MD
Protocol Approval – Sponsor Signatory 
 
Study Title 
A MulticeNter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Phase 3 Study to Evaluate the Efficacy and Safety of 
OV101 in PediaTric IndividUals With AngelmaN SyndromE 
(NEPTUNE) 
Protocol Number OV101-19-001 
 
Amendment 5 
 
Version 6.0 
Date: 
26 January 2021 
Protocol accepted and approved by: 
 
 
 
 
 
 
03 February 2021 
Date 
New York, NY 10036
1460 Broadway
Ovid Therapeutics Inc.
Vice President, Clinical Development
Signature
Signature
Signature


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Christopher J. Keary, MD
Coordinating Investigator
Protocol Approval –Coordinating Investigator 
 
Study Title 
A MulticeNter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Phase 3 Study to Evaluate the Efficacy and Safety of 
OV101 in PediaTric IndividUals With AngelmaN SyndromE 
(NEPTUNE) 
Protocol Number OV101-19-001 
 
Amendment 5 
 
Version 6.0 
Date: 
26 January 2021 
Protocol accepted and approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature
 
Date
ckeary@partners.org
Fax: 781-860-1766
Telephone: 781-860-1729
1 Maguire Rd, Lexington, MA 02421
Instructor, Harvard Medical School
Assistant in Psychiatry, Lurie Center/Mass General Hospital for Children
Child, Adolescent and Adult Psychiatrist


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Ying Yan, PhD
Signature
Date
Protocol Approval – Lead Statistician 
 
Study Title 
A MulticeNter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Phase 3 Study to Evaluate the Efficacy and Safety of 
OV101 in PediaTric IndividUals With AngelmaN SyndromE 
(NEPTUNE) 
Protocol Number OV101-19-001 
 
Amendment 5 
 
Version 6.0 
Date: 
26 January 2021 
Protocol accepted and approved by: 
 
 
 
 
 
 
 
 
New York, NY 10036
1460 Broadway
Ovid Therapeutics Inc.
Vice President, Biostatistics, Programming & Data Mgt
Date
Signature


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
 
 
Protocol Amendment 5 (Version 6.0) Summary of Changes 
Rationale for Amendment 5 
 
Protocol Amendment 5 (Version 6.0) includes administrative changes only to clarify the 
serious adverse event reporting process for subjects that do not elect to enter the open-label 
extension study (Section 6.4.1.5). 
 
Changes Implemented With Amendment 5: 
 
Section 6.4.1.5 (new text in bold/underlined type; no deletions were made in this 
amendment): 
 
All SAEs must be reported starting from the time that informed consent for study 
participation is provided. If the investigator becomes aware of an SAE within 30 days after 
the subject’s last dose of study drug or within 30 days after the last study visit, the SAE must 
be reported unless the patient has signed the consent to enroll into the ELARA open 
label extension study. Serious AEs must be followed until the event resolves, the event or 
sequelae stabilize, or it is unlikely that additional information can be obtained after 
demonstration of due diligence with follow-up efforts (i.e., the subject or health care 
practitioner is unable to provide additional information, or the subject is lost to follow-up). 
For subjects who do not sign the informed consent to enroll into the ELARA open label 
extension study, serious AEs that occur more than 30 days after the last dose of study drug 
should be submitted to the sponsor if the investigator becomes aware, however, these do not 
need to be reported to the IRB/EC or regulators unless the investigator or Sponsor considers 
them related to study drug. 


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
 
 
Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A MulticeNter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Study to Evaluate the Efficacy 
and Safety of OV101 in PediaTric IndividUals With AngelmaN SyndromE (NEPTUNE)” 
and the accompanying Investigator’s Brochure. 
 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the current protocol (Version 1.0, dated 30 May 2019), the International 
Council for Harmonisation harmonised tripartite guideline E6 (R2): Good Clinical Practice 
and all applicable government regulations. I will not make changes to the protocol before 
consulting with Ovid Therapeutics Inc. or implement protocol changes without independent 
ethics committee approval except to eliminate an immediate risk to subjects. I agree to 
administer study treatment only to subjects under my personal supervision or the supervision 
of a sub investigator. 
 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or 
appear in any study reports or publications. 
 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Ovid Therapeutics Inc. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
Printed Name of Principal Investigator
 
 


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Table of Contents 
CLINICAL STUDY PROTOCOL ........................................... Error! Bookmark not defined. 
Table of Contents ....................................................................................................................... 7 
List of Tables ........................................................................................................................... 11 
Protocol Synopsis ..................................................................................................................... 12 
List of Abbreviations ................................................................................................................ 30 
Definition of Terms .................................................................................................................. 31 
1 
Introduction ....................................................................................................................... 32 
2 
Study Objectives ............................................................................................................... 36 
2.1 
Primary Objective ................................................................................................... 36 
2.2 
Secondary Objectives .............................................................................................. 36 
2.5 
Safety Objectives ..................................................................................................... 37 
3 
Investigational Plan .......................................................................................................... 38 
3.1 
Study Design ........................................................................................................... 38 
4 
Subject Selection and Withdrawal Criteria ....................................................................... 42 
4.1 
Selection of Study Population ................................................................................. 42 
4.1.1 
Inclusion Criteria ...................................................................................... 42 
4.1.2 
Exclusion Criteria .................................................................................... 44 
4.2 
Discontinuation and Withdrawal of Subjects .......................................................... 45 
4.2.1 
Reasons for Withdrawal ........................................................................... 46 
4.2.2 
Handling of Withdrawals ......................................................................... 46 
4.2.3 
Replacements ........................................................................................... 47 
5 
Study Treatments .............................................................................................................. 48 
5.1 
Method of Assigning Subjects to Treatment Groups .............................................. 48 
5.2 
Treatment Administration ........................................................................................ 49 
5.2.1 
Dose Titration ........................................................................................... 50 
5.3 
Identity of Investigational Product .......................................................................... 51 
5.4 
Management of Clinical Supplies ........................................................................... 51 
5.4.1 
Study Drug Packaging and Storage ......................................................... 51 
2.3
2.4
Pharmacokinetic Objectives .................................................................................... 37
Tertiary Objectives .................................................................................................. 37
Rationale of Dosing ................................................................................. 39
3.1.1
2.3
2.4


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5.4.2
Test Article Accountability ....................................................................... 52 
5.4.3
Other Supplies .......................................................................................... 52 
5.5 
Overdose Management ............................................................................................ 52 
5.5.1
Treatment of Overdose ............................................................................. 52 
5.5.2
Medication Errors .................................................................................... 52 
5.5.3
Treatment of Medication Errors ............................................................... 53 
5.6 
Blinding ................................................................................................................... 53 
5.6.1
Breaking the Blind ................................................................................... 53 
5.7 
Treatment Compliance ............................................................................................ 54 
5.8 
Prior and Concomitant Therapy .............................................................................. 54 
5.8.1
Prohibited Medications and Therapies ..................................................... 55 
5.8.2
Restrictions ............................................................................................... 55 
6
Study Assessments and Procedures .................................................................................. 56 
6.1 
Screening Assessments ............................................................................................ 59 
6.2 
Efficacy Assessments .............................................................................................. 59 
6.2.1
Efficacy Assessments ............................................................................... 59 
6.2.1.1
Clinical Global Impressions Scales .......................................................... 59 
6.2.1.2
Vineland Adaptive Behavior Scale, 3rd Edition ........................................ 59 
6.2.1.3
Children’s Sleep Habits Questionnaire .................................................... 60 
6.2.1.4
Pediatric Quality of Life Inventory .......................................................... 60 
6.2.2
Actigraphy ................................................................................................ 61 
6.2.3
Sleep Diary ............................................................................................... 61 
6.3 
6.4 
Safety Assessments..................................................................................................62 
6.4.1
Adverse Events ........................................................................................63 
6.4.1.1
Definitions of Adverse Events .................................................................63 
6.4.1.2
Serious Adverse Events ............................................................................64 
6.4.1.3
Eliciting and Documenting Adverse Events ............................................65 
6.4.1.4
Reporting Adverse Events ........................................................................65 
6.4.1.5
Reporting Serious Adverse Events ...........................................................66 
6.4.1.6
Suspected Unexpected Serious Adverse Reactions and Nonserious 
Adverse Events of Special Interest ..........................................................67 
6.4.1.7
Assessment of Severity ............................................................................67 
6.4.1.8
Assessment of Causality ..........................................................................68 
6.4.1.9
Follow-Up of Subjects Reporting Adverse Events ..................................69 
6.4.2
Other Safety Assessments ........................................................................69 
6.4.2.1
Assessment of Suicidality ........................................................................69 
Pharmacokinetic Assessments ................................................................................. 62
................................................................................................ 61
Pediatric Quality of Life Inventory .......................................................... 60
Sleep Diary ............................................................................................... 61
Children’s Sleep Habits Questionnaire .................................................... 60
Actigraphy .
6.2.2
6.2.1.4
6.2.3
6.2.1.3


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6.4.2.2
Seizure Diary............................................................................................ 69 
6.4.2.3
Vital Sign Measurements ......................................................................... 70 
6.4.2.4
Physical Examinations ............................................................................. 70 
6.4.2.5
Exposure During Pregnancy and/or Lactation ......................................... 70 
6.5 
Safety Monitoring Committee ................................................................................. 71 
6.6 
Pregnancy ................................................................................................................ 71 
6.7 
Laboratory Analyses ................................................................................................ 73 
6.8 
Sample Collections .................................................................................................. 73 
6.9 
Contraception and Pregnancy Avoidance Procedure ............................................... 74 
7
Statistical and Analytical Plan .......................................................................................... 75 
7.1 
General Considerations ........................................................................................... 75 
7.2 
Endpoints ................................................................................................................. 75 
7.2.1
Efficacy Endpoints ................................................................................... 75 
7.2.1.1
Primary Endpoint ..................................................................................... 75 
7.2.1.2
Key Secondary Endpoints ........................................................................ 75 
7.2.1.3
Other Secondary Endpoints ...................................................................... 75 
7.2.2
Safety Endpoints ...................................................................................... 77 
7.2.3 
7.3 
Sample Size and Power ........................................................................................... 78 
7.4 
Analysis Sets ........................................................................................................... 79 
7.5 
Subject Disposition ................................................................................................. 80 
7.6 
Demographic and Baseline Characteristics ............................................................. 80 
7.7 
Exposure and Compliance ....................................................................................... 80 
7.8 
Efficacy Analyses .................................................................................................... 81 
7.8.1
Primary Efficacy Analyses ....................................................................... 81 
7.8.2
Key Secondary Efficacy Analyses ........................................................... 82 
7.8.3
Other Secondary Analyses ....................................................................... 82 
7.8.5 
Description of Subgroups to be Analyzed ................................................ 84 
7.9 
Safety Analyses ....................................................................................................... 84 
7.9.1
Adverse Events ........................................................................................ 84 
7.9.2
Clinical Laboratory Tests ......................................................................... 84 
7.9.3
Vital Signs and Physical Examinations .................................................... 85 
7.9.4
Suicidality ................................................................................................ 85 
Tertiary Analyses ...................................................................................... 83
7.8.4
Pharmacokinetic Endpoints ...................................................................... 77
Tertiary Endpoints .................................................................................... 76
7.2.1.4


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7.9.5
Seizure Diary Data ................................................................................... 85 
7.10 Other Analyses ........................................................................................................ 85 
7.10.1
Concomitant Medications ........................................................................ 85 
7.10.2 
7.11 Interim Analyses ...................................................................................................... 86 
7.12 Statistical Testing and Significance Level ............................................................... 86 
7.13 Missing Data Handling and Sensitivity Analysis .................................................... 87 
8
Data Quality Assurance .................................................................................................... 88 
8.1 
On-Site Audits ......................................................................................................... 88 
8.2 
Data Management ................................................................................................... 88 
9
Ethics ................................................................................................................................ 90 
9.1 
Independent Ethics Committee or Institutional Review Board ............................... 90 
9.2 
Ethical Conduct of the Study .................................................................................. 90 
9.3 
Subject Information and Consent ............................................................................ 90 
10
Investigator’s Obligations ................................................................................................. 92 
10.1 Confidentiality ......................................................................................................... 92 
10.2 Financial Disclosure and Obligations...................................................................... 92 
10.3 Investigator Documentation .................................................................................... 92 
10.4 Study Conduct ......................................................................................................... 93 
10.5 Adherence to Protocol ............................................................................................. 93 
10.6 Adverse Events and Study Report Requirements .................................................... 93 
10.7 Investigator’s Final Report ...................................................................................... 93 
10.8 Records Retention ................................................................................................... 94 
10.9 Publications ............................................................................................................. 94 
11
Study Management ........................................................................................................... 95 
11.1 Monitoring ............................................................................................................... 95 
11.1.1
Independent Data Monitoring Committee ............................................... 95 
11.1.2
Clinical Trial Steering Committee ........................................................... 95 
11.1.3
Monitoring of the Study ........................................................................... 96 
11.1.4
Inspection of Records ............................................................................... 96 
11.2 Management of Protocol Amendments and Deviations .......................................... 97 
11.2.1
Modification of the Protocol .................................................................... 97 
11.2.2
Protocol Deviations .................................................................................. 97 
Pharmacokinetic Analyses ....................................................................... 86


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Table 3–1
in Adults Receiving an OV101 Dose of 15 mg................................................40
Receiving Predicted Exposure-Matched OV101 Doses vs Observed Exposures
Predicted Exposure Parameters in Pediatric Subjects at Various Ages
Table 3–2
Doses of OV101 for Pediatric Subject Body Weight Ranges ..........................40
Model-Predicted Exposure (AUC0-∞ and Cmax) on Days 1 and 5 After Fixed
Table 5–1
Daily Dosing and Titration of OV101 by Weight ............................................49
Table 5–2
Down-Titration of OV101 by Weight ..............................................................51
Table 6–1
Schedule of Activities .......................................................................................56
11.3 Study Termination ................................................................................................... 97 
11.4 Final Report ............................................................................................................. 98 
12
Reference List ................................................................................................................... 99 
13
Pandemic Addendum ...................................................................................................... 101 
List of Tables 
 
 
 
 


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Protocol Synopsis 
 
Protocol Number:
OV101-19-001 
Title: 
A MulticeNter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 
Study to Evaluate the Efficacy and Safety of OV101 in PediaTric IndividUals With 
AngelmaN SyndromE (NEPTUNE) 
Sponsor: 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
Study Phase: 
Phase 3 
Study Sites: 
Approximately 15 study sites in the United States, Israel, Australia and/or Europe 
Indication: 
Angelman syndrome (AS) 
Rationale: 
Angelman syndrome is a severe, complex, and rare neurogenetic disorder with a prevalence 
estimated at 1 in every 10,000 to 24,000 live births. The condition is associated with 
impaired expression of the ubiquitin protein ligase E3A gene (UBE3A). While ubiquitin 
protein ligase E3A (Ube3a) is expressed from both gene copies in the cells of other tissues, in 
neurons the paternal allele is preferentially silenced through the epigenetic process known as 
imprinting. Therefore, any alteration in the maternal copy of UBE3A results in AS. Clinical 
findings range in severity and include developmental delay/intellectual disability, movement 
and/or balance disorder, and tremulous movement of limbs. Unique behavioral characteristics 
include the combination of a happy, smiling demeanor with easily provoked laughter and 
excitability (exhibited by hand-flapping and stereotypic movements). Individuals with AS 
frequently have motor dysfunction related to gait and balance, severe disruptions in sleep, 
little to no speech, short attention span, anxiety, and seizures with characteristic abnormal 
electroencephalogram patterns. 
Current treatments are aimed at managing symptoms and include antiepileptic medications 
for seizure control and medications for sleep and behavioral problems (e.g., anxiety). Other 


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therapies include speech therapy, physical therapy, occupational therapy, and educational 
resources. Notably, current treatments do not target the underlying brain deficits. 
 
OV101 is the first highly-selective, extrasynaptic gamma-aminobutyric acid (GABA) 
receptor agonist that binds as an orthosteric agonist to the α4- and δ-containing subunit of 
extrasynaptic GABA receptors. Research has shown that absence (or dysfunction) of Ube3a 
results in an aberrant increase in the uptake of GABA, which is the main inhibitory 
neurotransmitter in the brain. The extrasynaptic GABA receptors mediate tonic inhibition and 
sleep maintenance. In a mouse model of AS, OV101 was shown to restore tonic inhibition in 
Ube3a-deficient cerebellar neurons and correct motor abnormalities in Ube3a-deficient mice. 
These results suggest that OV101 may alleviate the motor dysfunction observed in 
individuals with AS. Importantly, OV101’s ability to potentiate tonic inhibition is unlike any 
other GABAergic agent, including benzodiazepines, zolpidem, zaleplon, zopiclone, 
barbiturates, neurosteroids, and drugs that act on GABA metabolism or uptake. Unlike many 
of these drugs that are allosteric modulators and therefore require endogenous GABA to 
function, OV101 is a GABA agonist and can function when GABA is deficient or absent. In 
addition to the data on presynaptic dysfunction leading to reduced tonic inhibition, there are 
additional studies which speak to the potential of OV101 in AS, including modulation of 
sleep and cognition domains that are impaired in subjects with AS. 
 
Phase 2 and Phase 3 studies in adult subjects with primary insomnia demonstrated that 
OV101 is effective in restoring classical sleep parameters (sleep induction and sleep 
maintenance) and slow wave sleep, resulting in an improvement in the quality and restorative 
effects of sleep. 
 
A randomized, double-blind, placebo-controlled Phase 2 study (OV101-15-001[STARS]; 
NCT02996305) evaluated the safety, tolerability, and exploratory efficacy measures of 
OV101 in adolescents and adults with AS over 12 weeks of treatment. The STARS study was 
the first industry-sponsored clinical study in AS. Overall, OV101 had a favorable safety 
profile and was well tolerated. OV101 had a statistically significant effect on the CGI-I, a 
measure of global function, included as an exploratory measure. Exploratory and post-hoc 
analyses suggested that improvements seen on the CGI-I were likely driven by sleep, gross 
and fine motor function, behavior, and communication. 
 
NEPTUNE (OV101-19-001) will be a multicenter, randomized, placebo-controlled, 
parallel -group study to evaluate the efficacy and safety of OV101 in pediatric subjects with 
AS. Subjects who complete the study will be eligible to enroll in the ongoing OV101-18-002 
(ELARA) open-label extension study, provided they meet the eligibility criteria for ELARA. 


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The tertiary efficacy objectives of this study are to evaluate the efficacy of OV101 versus
Tertiary Objectives:
x
on total sleep time and total activity assessed by actigraphy
x
based on sleep diary data (caregiver reported)
x
based on the Children’s Sleep Habits Questionnaire (CSHQ)
x
Multidimensional Fatigue, and Family Impact modules).
based on the Pediatric Quality of Life Inventory™ (Peds QL™) (Cerebral Palsy,
Objectives: 
All efficacy study objectives will be assessed in the pediatric AS study population of subjects 
who are 4 to 12 years old. All safety study objectives will be assessed in the pediatric AS 
study population of subjects who are 2 to 12 years old. 
Primary Objective: 
x To evaluate the efficacy of OV101 versus placebo as assessed by the Clinical Global 
Impressions-Improvement-Angelman syndrome (CGI-I-AS) score at Week 12. 
Key Secondary Objectives: 
The purpose of the key secondary objectives is to fulfil a recommendation of the EMA for a 
responder analysis. 
x To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of 
subjects who experience any meaningful improvement on study treatment (defined as 
CGI-I-AS score of 1, 2, or 3 at Week 12) 
x To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of 
subjects who experience a response of much improved or very much improved 
(defined as CGI-I-AS score of 1 or 2 at Week 12) 
Other Secondary Objectives: 
Other secondary efficacy objectives of this study are: 
x

x To evaluate the efficacy of OV101 versus placebo on Communications, Socialization, 
Daily Living Skills, Motor Skills, and Maladaptive Behavior domains assessed by the 
Vineland Adaptive Behavior Scale, 3rd Edition (VABS-3). 
x To evaluate the efficacy of OV101 versus placebo based on the Clinical Global 
Impressions-Severity-Angelman syndrome (CGI-S-AS) Symptoms Overall score. 
x To evaluate the relationships of CGI-S-AS Symptoms Overall and CGI-S-AS 
domains at baseline with CGI-I-AS at Week 12. 
 
 
placebo:
sleep efficiency, and daytime sleep assessed by actigraphy.
To evaluate the efficacy of OV101 versus placebo on latency of sleep onset (LSO),
x
x
x
x


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It is acknowledged that pharmacokinetic sampling may be unduly burdensome for some sites
to perform in this patient population and may therefore not be performed in some subjects.  
Where a site is unable to perform PK sampling, this should be discussed with the Medical 
Monitor or Sponsor, documented and captured in the Trial Master File.  
Safety Objectives: 
The safety objectives of this study are to evaluate the safety and tolerability of OV101 in 
subjects 2 to 12 years old, including seizure diary data and assessment of suicidality. 
physiologically-based PK (PBPK) model for the pediatric study population 2 to 12 years old.
approach as well as to evaluate estimated PK parameters in the context of a validated
curve [AUC]) following a single oral dose using sparse sampling and a population PK
to OV101 (maximum plasma concentration [Cmax] and area under the concentration-time
The pharmacokinetic (PK) objectives of this study are to estimate systemic plasma exposure
Pharmacokinetic Objectives:


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Study Population: 
Inclusion Criteria: 
Each subject must meet all the following criteria to be enrolled in this study: 
1. Is male or female and 2 to 12 years old (inclusive) at the time of informed 
consent. 
2. Has a diagnosis of AS with molecular confirmation. 
3. Has a CGI-S-AS score of 3 or more. 
4. Meets the following age-appropriate body weight criterion: 
a) Subjects 2 to 3 years old must have a minimum body weight of 9 kg. 
b) Subjects 4 years and older must be between 17 kg and 64 kg (inclusive). 
5. Has a legally acceptable representative (LAR)/caregiver capable of providing 
written informed consent and able to attend all scheduled study visits, oversee the 
administration of study drug, and provide feedback regarding the subject’s 
symptoms and performance as described in the protocol. 
6. Provides assent to the protocol (to the extent possible and in accordance with 
local institutional review board [IRB] and regulatory requirements). Subjects 
providing assent must do so at the same visit as LAR/caregiver written informed 
consent is provided. 
7. Can swallow study drug capsules with water or ingest the contents of study drug 
capsules after sprinkling the contents of each capsule onto up to 1 teaspoon of 
low-fat semiliquid food. 
8. If a subject is currently receiving a regimen of concomitant medications such as 
antiepileptic medication, gabapentin, clonidine, trazodone, melatonin, or a 
special diet regimen, that subject’s regimen is stable for at least 4 weeks before 
Day 1 (first day of study drug administration) and will be maintained throughout 
the duration of the study (in the judgment of the investigator). 
9. If a subject is a sibling in a family with multiple children diagnosed with AS, 
then only one of the siblings may enroll in study. The eldest eligible subject 
should be enrolled (investigator discretion may be used to enroll a younger 
sibling instead). 
10. Has LAR(s)/caregiver(s) who agree not to post any of the subject’s personal 
medical data or information related to the study on any website, message 
board(s), online support group(s), or social media site (e.g., Facebook, Instagram, 
Twitter, etc.) until notified that the study is completed. 
11. Female subjects who are of child-bearing potential (defined as having 
experienced their first menarche) must agree to use either a highly effective or 
acceptable form of birth control during the study and for 30 days following the 
last dose of the study. Highly effective contraceptive methods are as follows: 
a. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
 Oral 
 Intravaginal 


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 Transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
 Oral 
 Injectable 
 Implantable 
c. Intrauterine device 
d. Intrauterine hormone-releasing system 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Sexual abstinence 
 
Acceptable birth control methods that result in a failure rate of more than 1% per 
year include: 
a. Progestogen-only oral hormonal contraception, where inhibition of ovulation 
is not the primary mode of action. 
b. Male or female condom with or without spermicide. 
c. Cap, diaphragm, or sponge with spermicide. 
d. A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods. 
 
Exclusion Criteria: 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Has a circumstance or concomitant disease (e.g., gastrointestinal, renal, hepatic, 
endocrine, respiratory, or cardiovascular system disease), condition, or any 
clinically significant finding at screening that could interfere with the conduct of 
the study or that would pose an unacceptable risk to the subject in the opinion of 
the investigator. 
2. Has poorly controlled seizures defined as any of the following: 
a. Weekly seizures of any frequency with a duration more than 3 minutes. 
b. Weekly seizures occurring more than 3 times per week, each with a duration 
of less than 3 minutes. 
c. Investigator assessment. 
3. Has any of the following laboratory abnormalities: total bilirubin >1.5 × upper 
limit of normal (ULN), unless known Gilbert’s syndrome; alanine 
aminotransferase or aspartate aminotransferase >2.5 × ULN; serum creatinine 
>1.2 × ULN; absolute neutrophil count <1.5 × 109/L; platelets <80 × 109/L; 
hemoglobin <80 g/L; or thyroid-stimulating-hormone >1.25 × ULN or 
<0.8 × lower limit of normal. Retesting of clinical laboratory parameters may be 
allowed after consultation with the medical monitor or designee. 
4. Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, 
or ramelteon for sleep, or minocycline or levodopa within the 4 weeks prior to 


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 18 
 
 
 
Day 1 or during the study. Benzodiazepines administered as needed for 
situational anxiety related to occasional procedures or events are permitted, and 
benzodiazepines are also permitted for seizure control. 
5. 
 
 
6. Is at risk of harming self and/or others (based on investigator assessment). 
7. Has enrolled in any other interventional clinical study or used any investigational 
agent or device, or has participated in any investigational procedure, within the 
30 days before screening or does so concurrently with this study. 
8. Is allergic to OV101 or any excipients of study drug. 
9. The subject or LAR/caregiver is unable to comply with study requirements 
(based on investigator assessment). 
10. Is a family member of the investigator and/or study site staff. 
3 attempts.
consecutive weekend days) during the 28-day screening period of the study, after
Cannot tolerate wearing the actigraph for at least 7 consecutive days (including 2


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 19 
 
 
On Day 1, subjects will take their first dose of study drug at the study site during the daytime,
and blood will be sampled 45 minutes ± 15 minutes, 90 minutes ± 15 minutes and 4 hours ± 
Study Design: 
The study will comprise a screening period within the 28 days preceding Day 1; a visit on 
Day 1 for baseline assessments, the first dose of study drug, and sparse sampling of blood; 
subsequent doses of study drug taken each evening approximately 30 minutes before bedtime 
for 12 weeks starting on Day 2; and study site visits for efficacy and safety assessments over 
a 12-week treatment period. After the baseline visit, the study site visits will occur at Week 6 
and Week 12 (end of treatment [EOT]). Phone safety visits will occur during up-titration of 
the study drug (Day 6 and Day 11). Unless a subject decides to participate in the ELARA 
open-label extension study, an end of study (EOS) phone safety visit will occur 
approximately 2 weeks after the last dose of study drug to assess safety and tolerability 
associated with discontinuation of treatment. Subjects eligible for and willing to enroll in the 
ELARA study will have the NEPTUNE EOT visit be their NEPTUNE EOS visit, and their 
NEPTUNE EOT visit will serve as their ELARA baseline visit. A subject will be considered 
to have completed the NEPTUNE study after completing the EOS visit. The total duration of 
the study for a subject will be approximately 18 weeks. 
Random assignment of subjects for efficacy assessment (to either OV101 or placebo 
treatment in a 1:1 ratio) will be stratified by subject age at screening and by region, with a 
maximum of 12 subjects per study site (unless authorized by Sponsor). The randomization 
strata for age at screening will be 9 to 12 years old (inclusive) and 4 to 8 years old 
(inclusive), with at least 24 subjects per age category. The randomization strata for region 
will be US and outside US. Approximately 5 subjects 2 to 3 years old (inclusive) will be 
enrolled for safety and PBPK assessments only and will be assigned to treatment with 
OV101. Within each age group, dosing will be assigned based on body weight at screening. 
For each subject, after informed consent is obtained, screening assessments will be 
completed within the 28 days preceding Day 1 (baseline). On Day 1, each subject who meets 
all eligibility criteria will receive the first assigned blister cards of study drug capsules 
according to the treatment code (except for subjects 2 to 3 years old, who will receive study 
drug capsules in bottles), sufficient to last until the Week 6 visit, when blister cards (or 
bottles for ages 2 to 3 years) will be collected and unused study drug will be counted. Study 
drug will be similarly dispensed at the Week 6 visit, and blister cards  (or bottles for ages 
2 to 3 years) will be collected and unused study drug will be counted at the Week 12 visit. 
Caregivers/LARs will be provided an additional blister card in case of unexpected delays for 
study visits (e.g., inclement weather/flight delays). 
and PBPK 


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 20 
 
 
Subject assignment to treatment will be stratified and staged by age and gated by an
 
 
 
 
Each subject’s dose of study drug (OV101 or placebo) will be adjusted from the starting dose
to the maintenance dose according to the titration schedule, as tolerated by the subject. On
Days 1 through 5, each subject will receive the starting dose. On Day 6, each subject will up-
titrate to the maintenance dose. Phone calls to assess tolerability will occur on Day 6 and
Day 11. The maintenance dose will be set based on the subject’s weight at screening and will
be continued to the EOT.  
Downward dose adjustments may be permitted to mitigate tolerability concerns with OV101.
These adjustments will be at the investigator’s discretion and should be discussed with the  
medical monitor or his/her delegate. Unscheduled study site visits are optional at any time to 
confirm tolerability.  
 
 
 
 
 
 
 
 
 
 
 
 
 
The LARs/caregivers will complete sleep diaries on behalf of subjects over the periods where
the subject is scheduled to wear the actigraph. An actigraph will be issued to each subject at  
the screening visit, so that actigraphy data can be collected for 7 consecutive days before
travel for the baseline visit. Subjects will be given 3 attempts within the 28-day screening
window to wear the actigraph for at least 7 consecutive days, and subjects will be excluded 
after 3 unsuccessful attempts to wear the actigraph for 7 consecutive days. Actigraphy data
collected during the first 7-consecutive day period that includes 2 weekend days during  
screening will be used as the baseline actigraphy assessment. These 7 consecutive days
during the review).
2 to 3 years old may begin treatment (initiation of treatment in the 4 to 8 age group continues
review and approval of the tolerability in the sentry subjects 4 to 8 years old, subjects
treatment in the 9 to 12 age group continues during the review). Similarly, following IDMC
PK acceptable, subjects 4 to 8 years old at screening may begin treatment (initiation of
forwarded to the IDMC for review as blinded data. If the IDMC considers the tolerability and
of the sentry subjects at Day 11, 5 days after initiation of the maintenance dose, will be
tolerability and PK in sentry subjects in the previous older cohort. The tolerability assessment
termed “sentry subjects.” No age cohort may begin treatment without IDMC review of
least 3 evaluable OV101 PK samples in each efficacy age group and these subjects will be
will begin treatment first. Initial enrollment of randomized subjects will be used to collect at
Independent Data Monitoring Committee (IDMC). Subjects 9 to 12 years old at screening
before anticipated bedtime, starting with the evening of Day 2.
population PK modeling). Subjects will take all subsequent doses approximately 30 minutes
30 minutes after dosing for determination of OV101 concentrations (sparse sampling for


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 21 
 
 
should include 2 consecutive weekend days and should not include any travel days. The 
actigraph it is to be worn for a maximum of 14 days preceding travel for the scheduled study 
site visits at Week 6 and Week 12 visits to collect at least 7 consecutive days of data 
including 2 consecutive weekend days. If the subject requires an additional attempt to keep 
the actigraph on for 7 consecutive days (including 2 consecutive weekend days) after the 
Week 6 visit, the subject will be given an actigraph to be worn for 7 days after Week 6. 
The LAR/caregivers will complete paper seizure diaries on behalf of subjects throughout the 
study, from issuance during screening (and at study visits) through Week 12 (EOT). 
Safety information will be collected during phone calls on Day 6 and Day 11 and during the 
EOS visit, as well as during every study site visit. Each subject’s LAR/caregiver will be 
instructed to contact the study center if the subject experiences any adverse events (AEs), is 
unable to take the study drug as prescribed, or is unable to tolerate wearing the actigraph. 
At the investigator’s discretion throughout the study, subjects may be evaluated at 
unscheduled clinic visits for reasons related to subject safety. At unscheduled visits, subjects 
will be queried about AEs and changes in concomitant medications and evaluated for 
suicidality. Safety laboratory assessments may be conducted. Periodic interim review of 
safety data will be performed by the IDMC and as part of routine pharmacovigilance 
activities.  
Estimated Study Duration: 
After informed consent is obtained, screening assessments will be conducted within the 
4 weeks preceding baseline, followed immediately by treatment for 12 weeks and a 2-week 
follow-up period (for subjects not enrolling into the ELARA study), for a maximum duration 
of individual subject participation of 18 weeks. Four study site visits are scheduled for each 
subject. 
 
For subjects choosing to participate in the ELARA open-label extension study, the 
NEPTUNE EOT visit will coincide with the baseline visit for ELARA, and there will be only 
3 scheduled study site visits. For NEPTUNE subjects participating in ELARA, the EOS visit 
that occurs approximately 2 weeks after the EOT will take place in the ELARA study only. 
Efficacy Assessments: 
Efficacy assessments will include the CGI-I-AS; the CGI-S-AS; the VABS-3; the CSHQ; the 
Peds QL (Cerebral Palsy, Multidimensional Fatigue, and Family Impact modules); 
actigraphy; and sleep diary. 
Pharmacokinetic Assessments and Analysis: 
Pharmacokinetic Assessments and Analysis:
actigraphy; and sleep diary.
Peds QL (Cerebral Palsy, Multidimensional Fatigue, and Family Impact modules);
CSHQ; the
j
p
y
(
)
or is unable to tolerate wearing the actigraph.
Week 6 visit, the subject will be given an actigraph to be worn for 7 days after Week 6.
the actigraph on for 7 consecutive days (including 2 consecutive weekend days) after the
including 2 consecutive weekend days. If the subject requires an additional attempt to keep
site visits at Week 6 and Week 12 visits to collect at least 7 consecutive days of data
actigraph it is to be worn for a maximum of 14 days preceding travel for the scheduled study


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the EOS, OV101 concentration and time data obtained from sparse sampling in this study 
will subsequently be subjected to population PK modeling and resulting exposure estimates 
will be evaluated using validated physiologically-based PK (PBPK) modeling to confirm  
predicted exposure estimates for the pediatric study population 2 to 12 years old at various 
weight bands. The population PK OV101 plasma exposure parameters will be further  
evaluated using a PBPK model specific for OV101 that was developed using a commercially
available PBPK software platform applied to extant PK data from adult and adolescent  
subjects. The PBPK modeling details will be reported separately. In addition to Cmax and 
AUC exposure estimates, elimination half-life and Tmax values may also be estimated.  
It is acknowledged that pharmacokinetic sampling may be unduly burdensome for some sites
to perform in this patient population and may therefore not be performed in some subjects.  
Where a site is unable to perform PK sampling, this should be discussed with the Medical  
Monitor or Sponsor, documented and captured in the Trial Master File.  
obtained previously from adolescents.
IDMC to confirm that individual OV101 concentration-time data align with respective data
4 to 8 years of age). Plasma concentrations within each time window will be evaluated by the
minimum of 3 evaluable sentry subjects receiving OV101 within each age band (9 to 12 and
for each of the above 3 time points following the initial dose will be determined from a
bioanalytical facility using a validated bioanalytical assay. Plasma concentrations of OV101
The PK samples will be analyzed for OV101 concentrations by a Sponsor-contracted
will be frozen, stored and shipped according to instructions to be provided to the study site.
during Day 1. Blood samples will be processed to plasma within 2 hours. Plasma samples
necessary. Approximately 2 mL of blood will be collected per PK sample for a total of 6 mL
blood sampling. Topical application of a cooling agent or local anesthetic is permitted if
and 4 hours ± 30 minutes. Study site staff will record the time of dosing and the time of
3 time points following the initial dose: 45 minutes ± 15 minutes; 90 minutes ± 15 minutes
daytime, and blood will be sampled for determination of plasma OV101 concentrations at
On Day 1, all subjects will take their first dose of study drug at the study site during the


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 23 
 
 
 
Safety Assessments: 
Safety assessments will include frequency, severity, and causality of AEs (including serious 
AEs [SAEs] and AEs leading to study discontinuation), and other safety assessments 
including assessment of suicidality (ABC-I), collection of seizure diaries, clinical laboratory 
assessments, vital sign measurements, and physical examinations. A total of up to 7 mL of 
blood is expected to be taken for laboratory measurements at each of screening, baseline, 
Week 6, and Week 12 visits. Total blood collected will not exceed 20 mL in a 30-day period. 
This is in accordance with the US Department of Health and Human Services, Office for 
Human Research Protections recommendations of 3 ml/kg, up to 50 ml total within 8 weeks 
(Table 2 in Howie 2011).  
 
Study Drug, Dosage, and Route of Administration: 
All doses of study drug will be administered orally. OV101 will be formulated as the 
monohydrate form of gaboxadol (4 ,5,6,7-tetrahydro-isoxazolo[5,4-c]-pyridin-3-ol,  
monohydrate) in white size 2 gelatin capsules, in 2-mg and 0.5-mg strengths (of the
anhydrous free zwitterion equivalent). Excipients will be microcrystalline cellulose and
 
Placebo capsules will be identical in appearance to the capsules containing OV101 and have 
the same excipient ingredients but will not contain the active compound. 
Study drug dosage will be assigned based on body weight at the screening visit. Study drug 
will be titrated from the starting dose to the maintenance dose according to Table 1. 
If at randomization on Day 1 a subject is assigned to placebo, the number of capsules per 
dose will correspond to the number of OV101 capsules for a subject of the same weight. 
Dosing will be initiated at the starting dose for the first 5 days. On Day 6, tolerability will be 
assessed by the investigator. If there are no tolerability concerns (e.g., excessive somnolence, 
dizziness, vomiting, negative behavior changes) and no AE related to the study drug has been 
observed since Day 1 by the LAR/caregiver or the investigator, then the dose of OV101 will 
be increased to the maintenance dose for the duration of the study. The maintenance dose 
identified at screening will remain consistent throughout the study. If tolerability concerns 
are observed on Day 6, the subject will discontinue study drug.  
Table 1
Daily Dosing and Titration of OV101 by Weight 
Band 
Weight Range 
at Screening
 
Starting Dose  
 
Maint Dose  
Maint Dose 
(mg/kg) 
(mg [capsules])
(mg [capsules])
 
Visit (kg)  
1 
 
45-64  
 
6 mg (3× 2 mg)  
 
10 mg (5× 2 mg)  
 
0.222–0.156  
magnesium stearate.
1
Maint Dose
(mg/kg) 
Weight Range
at Screening
Daily Dosing and Titration of OV101 by Weight
(mg [capsules])
g
(mg [capsules])
Band 
will be formulated as the


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 24 
 
 
Maintenance
Down-Titration of OV101 by Weight 
Maintenance
a
b
Must be <4 years of age at screening visit.
(mg/kg)
Band
(mg/kg)
Weight
Reduceda
Reduceda
(kg)
45-64
10 mg (5× 2 mg)
8 mg (4× 2 mg)
0.177–0.125
35-44
8 mg (4× 2 mg)
0.23–0.19
6 mg (3× 2 mg)
0.172–0.136
25-34
6 mg (3× 2 mg)
0.24–0.176
4 mg (2× 2 mg)
0.16–0.118
17-24
4 mg (2× 2 mg)
0.23–0.16
2 mg (1× 2 mg)
0.118–0.08
9-16b
2 mg (4× 0.5 mg)
0.23–0.125
1.5 mg (3× 0.5 mg)
0.167–0.09
The reduced dose results from a down-titration, 1 capsule less per day. 
5 
4 
3 
2 
0.222–0.156 
1 
visit
Maintenance Dose
(mg [capsules]) 
Range at
screening 
Maintenance Dose 
(mg [capsules]) 
Table 2
Dose
Dose
2 
35-44 
4 mg (2× 2 mg) 
8 mg (4× 2 mg) 
0.23–0.19 
3 
 
25-34  
 
2 mg (1× 2 mg)  
 
6 mg (3× 2 mg)  
 
0.24–0.176 
4 
 
17-24 
 
2 mg (1× 2 mg)  
 
4 mg (2× 2 mg)  
 
0.23–0.16  
5 
 
9-16a  
 
1 mg (2× 0.5 mg) 
 
2 mg (4× 0.5 mg) 
 
0.23–0.125 
Abbreviation: Maint, maintenance.  
a 
The subject’s maintenance dose for the duration of the study will be set based on the subject’s 
weight at the screening visit, and the subject should continue taking the maintenance dose 
after the Day 6 assessment until the EOS. Tolerability will again be assessed during the Day 
11 phone call while the subject is taking the maintenance dose. The investigator may initiate 
down-titration on Day 11 by 1 capsule (Table 2) based on investigator assessments of 
tolerability and AEs, or medical necessity. If down-titration is initiated, then the investigator 
should reassess tolerability with the modified dose regimen within 3 days of the dosing 
change. No further changes in dose regimen should be made after Day 15. 
If tolerability is not acceptable at any other time during the 12 weeks of treatment, the 
investigator should discuss the situation with the medical monitor or his/her delegate. Any 
intolerability must be documented as an AE. The daily dose may not be lower for any subject 
than the reduced maintenance dose indicated in Table 2. If a subject cannot tolerate the 
reduced maintenance dose, that subject must discontinue treatment. Any dose adjustments or 
changes in dosing must be documented in the electronic case report form and supporting 
rationale must be documented in the medical record or other appropriate source document. 
Must be <4 years of age at screening visit.
a
5
4
3
2
0.23–0.19
8 mg (4× 2 mg)
4 mg (2× 2 mg)
35-44 
Must be <4 years of age at screening visit.
b
The reduced dose results from a down-titration, 1 capsule less per day.
a
5
4
3
2
1
(mg [capsules])
Maintenance Dose
Maintenance
(mg [capsules])
Maintenance
Maintenance Dose
Down-Titration of OV101 by Weight
g
Range at
screening 


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 25 
 
 
The sample size calculations are based on comparison of the CGI-I-AS score at Week 12
Assumptions are derived from the results observed in the OV101-15-001 Phase 2 study: a
As a sensitivity analysis of the assumption of normality, a Wilcoxon rank-sum test will be
Sample Size: 
Approximately 90 subjects 4 to 12 years old (inclusive) will be randomly assigned in a 1:1 
ratio into OV101 or placebo treatment groups for both efficacy and safety assessments. 
Randomization will be stratified by age categories: 9 to 12 years old (inclusive) and 4 to 8 
years old (inclusive), with at least 24 subjects per age category, and by region: US and 
outside US. Approximately 5 subjects 2 to 3 years old (inclusive) will be included and treated 
with OV101 for safety assessments only. Approximately 95 subjects will be enrolled in the 
study at approximately 15 study sites with no more than 12 subjects per study site (unless 
authorized by the Sponsor).  
Sample size calculations were performed to determine the number of subjects needed for
evaluation of efficacy using the primary efficacy endpoint as well as the two key secondary
endpoints. Based on these calculations, a minimum of 40 evaluable subjects per treatment
group are required to ensure sufficient power for significance testing using the primary and
both key secondary endpoints.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the primary analysis of CGI-I-AS shows a significant difference between OV101 QD and  
placebo, two key secondary endpoints, CGI-I-AS response (at least minimally improved) at
Week 12 and CGI-I-AS response (at least much improved) at Week 12 will be used to test the
difference between OV101 and placebo with a gated sequential testing procedure at a 2-sided
0.05 level of significance. Power calculations were performed based on chi-square test of  
QD group.
12 response category in the placebo group, and 0, 0.296, 0.37, 0.334, 0, 0, 0 in the OV101
0.074, 0.148, 0.704, 0.074, 0, 0 for the probability of each CGI-I Symptoms Overall at Week
(scaled 1-7) with probability distributions observed in OV101-15-001 Phase 2 study: 0,
0.05 level of significance. This calculation is based on the assumption of 7 ordered categories
treatment difference of OV101 versus placebo using a Wilcoxon rank-sum test at a 2-sided
conducted. With 40 subjects per treatment group, there would be 99% power to test the
treatment difference at a 2-sided 0.05 level of significance.
effect size of 1. With 40 subjects per treatment group, there would be 99% power to test the
Overall score at Week 12 with a common standard deviation of 0.8 points, which yields an
mean difference of 0.8 points between OV101 QD and placebo in the CGI-I Symptoms
between OV101 and placebo, using a two-sample t-test with equal variances.


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 26 
 
 
Assuming a 10% drop-out rate, 90 subjects 4 to 12 years old will be randomized to OV101 
QD and placebo (1:1 randomization). 
 
 
Endpoint  
Primary Endpoint 
CGI-I-AS 
CGI-I-AS At Least 
Minimally 
Improved 
CGI-I-AS At Least 
Much Improved 
 
Test Significance  
0.05 
0.05 
0.05 
Level, α  
1 or 2- Sided Test 
 
Two  
 
Two  
 
Two  
Assumptions  
μ₁ - μ₂=0.8 and 
π₁=0.21, π2=0.67 
π₁=0.07, π2=0.32 
 
 
σ=0.8 
Power (%) 
 
99%  
 
99%  
 
81.8%  
Sample Size per  
40 
40 
40 
Group, n 
n, assuming 10%  
45 
45 
45 
Dropout  
two proportions. Assumptions regarding response rates are based on the rates observed in
summarizes the power calculations for all three endpoints:
OV101-15-001 Phase 2 study. With 40 evaluable subjects, per treatment group, there would  
be 99% power to test the treatment difference of OV101 versus placebo based on the first key
secondary endpoint, CGI-I-AS response (at least minimally improved), assuming a response  
rate of 21% for placebo and 67% for OV101 QD. With 40 subjects per treatment group,  
there would be 81.8% power to test the treatment difference of OV101 versus placebo based  
on the second key secondary efficacy endpoint, CGI-I-AS response (at least much improved),
assuming a response rate of 7% for placebo and 32% for OV101 QD.  The following table  
Assuming a 10% drop-out rate, 90 subjects 4 to 12 years old will be randomized to OV101
QD and placebo (1:1 randomization).
45
45
45
40
40
40
π₁=0.07, π2=0.32
π₁=0.21, π2=0.67 
μ₁ - μ₂=0.8 and 
0.05
0.05
0.05
Improved 
Minimally 
CGI-I-AS At Least
Much Improved
CGI-I-AS At Least 
CGI-I-AS
Primary Endpoint


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 27 
 
 
 
Statistical Methods: 
All statistical analyses will be performed using SAS® Version 9.4 or higher. All clinical 
study data will be presented in subject data listings. Data summaries will be presented for all 
endpoints and will include descriptive statistics (number of subjects, mean, SD, first quartile, 
median, third quartile, minimum, and maximum) for continuous variables, and frequency and 
percentage for categorical and ordinal variables. If there are missing values, the number of 
missing will be presented, but without a percentage. For all analyses, ‘baseline’ will refer to 
the most recent non-missing value obtained immediately prior to administration of first dose. 
 
For the primary efficacy analysis, the CGI-I-AS will be analyzed as a continuous outcome 
variable. A Mixed Model Repeated Measures (MMRM) Analysis of Variance (ANOVA) 
model will be fitted using restricted maximum likelihood (REML) for CGI-I-AS with fixed 
effects for visit, randomized treatment, the visit-by-treatment interaction, age group, and 
region. An unstructured within subject-covariance structure will be specified as the first 
choice, and if the model fails to converge, alternative covariance structures will be tested as 
detailed in the SAP. If a structured covariance is used, then a robust sandwich estimator will 
be utilized for estimating the variance of the treatment effect estimate. From the model, the 
Week 12 difference between least squared means of OV101 and placebo groups will be 
presented along with the corresponding 95% confidence interval and 2-sided P value. 
 
Generalized Estimating Equations (GEE) method will be used for the analysis of key 
secondary endpoints: CGI-I-AS response (at least minimally improved) and CGI-I-AS 
response (at least much improved). GEE models will include the response variable at each 
visit as the dependent variable, and fixed effects for visit (Week 6 and Week 12), randomized 
treatment, the visit-by-treatment interaction, age group (randomization stratification variable: 
age 4 to 8 years versus age 9 to 12 years), and region (randomization stratification variable: 
US versus outside US). An unstructured working correlation for the binary outcome variable 
will be assumed for the model parameter estimation, and if the model fails to converge, 
alternative covariance structures will be tested as detailed in the SAP. If there is no response 
in either treatment arm at the Week 6 visit, the GEE model will be substituted with a logistic 
regression for the Week 12 CGI-I-AS response variable with effects for the randomized 
treatment and the two randomization stratification variables. From the model (GEE or 
logistic regression, as appropriate), the Week 12 odds ratio will be presented along with the 
corresponding 95% confidence interval and 2-sided P value. 
 
All other continuous efficacy endpoints with post baseline assessments at Week 6 and Week 
12 will be analyzed by an MMRM Analysis of Covariance (ANCOVA) model for the change 
from baseline for the endpoint fitted with fixed effects for visit, randomized treatment, the 


Ovid Therapeutics Inc. 
Protocol OV101-19-001 Version 6.0
OV101
26 January 2021
Page 28 
 
 
 
visit-by-treatment interaction, age group, region, and the corresponding baseline as a 
covariate. An unstructured within subject -covariance structure will be specified as the first 
choice, and if this analysis fails to converge, alternative covariance structures will be tested 
as detailed in the SAP. From the model, the Week 12 difference between least squared means 
of OV101 and placebo groups will be presented along with the corresponding 95% 
confidence interval and 2-sided P value. 
 
Endpoints based on composite and subdomain scores from VABS-3 assessments will be 
analyzed as continuous outcome variables using an ANCOVA model with effects for 
randomized treatment, age group, region, and the corresponding baseline as a covariate. A 
test for a significant treatment-by-baseline interaction will be performed in a separate model 
(including the above terms plus the interaction term), using a 0.100 alpha level. If the 
treatment-by-baseline interaction is significant, then the ANCOVA assumptions are violated 
and an ANOVA model will be used instead. From the final model(s), the difference between 
least squared means of OV101 and placebo groups will be presented along with the 
corresponding 95% confidence intervals and 2-sided P values. 
 
Descriptive statistics will be used to summarize all safety endpoints by treatment group. 
Two-sided 95% CIs will be presented where meaningful. Data summaries will be displayed 
for incidence of AEs, clinical laboratory variables, vital signs, body weight and body mass 
index, physical examinations, suicidality assessed by ABC-I, and seizure diary data. 
 
For AEs, all treatment-emergent AEs (TEAEs) will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarized by MedDRA system organ class 
and preferred term and treatment group. Detailed listings of TEAEs, SAEs, related AEs, and 
discontinuations due to AEs will be provided. The incidence of TEAEs, discontinuations due 
to TEAEs, drug-related, and serious TEAEs will be summarized. Incidence of TEAEs by 
severity and relationship to study drug will also be presented. Incidence of TEAEs will be 
summarized separately for subjects 2 to 3 years old (inclusive). Other safety data for subjects 
2 to 3 years old (inclusive) will only be presented in listings and will be displayed in 
by -subject graphs, as appropriate. 
 
For clinical laboratory tests, changes from baseline to each post baseline visit with respect to 
clinical chemistry and hematology results will be summarized descriptively. Each laboratory 
parameter will be classified as low, normal, or high relative to the parameter’s reference 
range and will be summarized with shift tables. Listings of subjects with abnormal results 
will be provided. 


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Vital signs, weight, and body mass index will be summarized descriptively at baseline and all 
post baseline study visits by treatment group. Change from baseline to all post baseline study 
visits will be summarized descriptively by treatment group. 
 
Physical examinations (general appearance; skin; head, ear, eye, nose, and throat; neck; 
lymph node; chest; heart; abdominal cavity; limb; central nervous system; and 
musculoskeletal) at baseline will be summarized. Shifts from baseline to post baseline study 
visits in each body system/site will be summarized by treatment group.  
 
Suicidality and seizure diary data will be summarized descriptively at baseline and all post 
baseline study visits by treatment group. Change from baseline to all post baseline study 
visits also will be summarized descriptively by treatment group. 
 
The  
population PK-derived exposure estimates (Cmax and AUC) and other parameters (if derived)  
will be summarized descriptively and geometric means and coefficients of variation will be  
presented. 
OV101 plasma concentrations will be summarized descriptively at each timepoint.


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List of Abbreviations 
 
Abbreviation
Definition
ABC-I 
Aberrant Behavior Checklist-Irritability subscale 
AE 
adverse event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AS 
Angelman syndrome 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve from 0 to infinite hours 
ß-hCG 
beta-human chorionic gonadotrophin 
BID 
twice daily 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CGI-I 
Clinical Global Impressions-Improvement 
CGI-I-AS 
Clinical Global Impressions-Improvement-Angelman syndrome 
CGI-S-AS 
Clinical Global Impressions-Severity-Angelman syndrome 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
clinical study report 
CTSC 
Clinical Trial Steering Committee 
eCRF 
electronic case report form 
EDC 
EMA 
electronic data capture 
European Medicines Agency 
EOS 
end of study 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
independent ethics committee 
IRB 
institutional review board 
LAR 
legally acceptable representative 
LSO 
latency of sleep onset 
MedDRA 
Medical Dictionary for Regulatory Activities 
maximum plasma concentration 
Cmax 
area under the concentration-time curve from 0 to infinite hours
area under the concentration-time curve
AUC0-∞ 
AUC 
latency of sleep onset 
LSO
Children’s Sleep Habits Questionnaire
CSHQ


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Abbreviation
Definition
MMRM 
Mixed Model Repeated Measures 
PBPK 
physiologically based pharmacokinetic 
Peds QL™ 
Pediatric Quality of Life Inventory™ 
PK 
pharmacokinetic(s) 
PPS 
per protocol set 
QD 
once daily 
SAE 
serious adverse event 
SAP 
SIF/DRF 
statistical analysis plan 
Seizure Identification Form and Diagnostic Review Form 
SS 
safety set 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum plasma concentration 
Ube3a 
ubiquitin protein ligase E3A 
UBE3A 
ubiquitin protein ligase E3A gene 
ULN 
upper limit of normal 
VABS-3 
Vineland Adaptive Behavior Scale, 3rd Edition 
 
 
 
 
Definition of Terms 
 
Term
 
Definition
Day 1 
 
The first day of study drug administration 
ELARA 
 
Study OV101-18-002, an open-label extension study 
NEPTUNE 
 
Study OV101-19-001 
OV101 
 
gaboxadol 
Ovid 
 
Ovid Therapeutics Inc. 
Sentry subject  
One of the initially enrolled subjects in an age group required for 
measuring PK, whose PK and tolerability data are reviewed by the 
Independent Data Monitoring Committee before subjects are enrolled 
in a younger age group 
STARS 
 
Study OV101-15-001 
time to maximum plasma concentration 
tmax 
t
One of the initially enrolled subjects in an age group required for 
measuring PK, whose PK and tolerability data are reviewed by the
Independent Data Monitoring Committee before subjects are enrolled 
in a younger age group
Sentry subject
pharmacokinetic(s)
physiologically based pharmacokinetic
™
Pediatric Quality of Life Inventory™
PK
PBPK
™
Peds QL™


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1 
Introduction 
Ovid Therapeutics Inc. (Ovid) is developing OV101 (gaboxadol) for the treatment of rare genetic 
disorders that are associated with severe developmental and behavioral challenges that have no 
approved therapies, such as Angelman syndrome (AS) and Fragile X syndrome. Gaboxadol was 
initially developed for the treatment of insomnia by H. Lundbeck A/S and Merck, but its 
development was discontinued in 2007. Extensive nonclinical and clinical data were generated 
during the initial stages of development, including data from exposure to gaboxadol in more than 
4,300 adult subjects with insomnia and approximately 500 adult subjects in 
non-insomnia -related studies. 
 
Angelman syndrome is a severe, complex, and rare neurogenetic disorder with a prevalence 
estimated at 1 in every 10,000 to 24,000 live births (Petersen et al 1995; Steffenburg et al 1996; 
Mertz et al 2013). The condition is associated with impaired expression of the ubiquitin protein 
ligase E3A gene (UBE3A). While UBE3A is expressed from both gene copies in the cells of other 
tissues, in neurons the paternal allele is preferentially silenced through the epigenetic process 
known as imprinting. Therefore, any alteration in the maternal copy of UBE3A results in AS. 
Clinical findings range in severity and include developmental delay/intellectual disability, 
movement and/or balance disorder, and tremulous movement of limbs. Unique behavioral 
characteristics include the combination of a happy, smiling demeanor with easily provoked 
laughter and excitability (exhibited by hand-flapping and stereotypic movements). Individuals 
with AS frequently have motor dysfunction related to gait and balance, severe disruptions in 
sleep, little to no speech, short attention span, anxiety, and seizures with characteristic abnormal 
electroencephalogram patterns (Williams et al 2006). 
 
Current treatments are aimed at managing symptoms and include antiepileptic medications for 
seizure control and medications for sleep and behavioral problems (e.g., anxiety). Other therapies 
include speech therapy, physical therapy, occupational therapy, and educational resources. 
Notably, current treatments do not target the underlying brain deficits. 
 
OV101 is the first highly selective, extrasynaptic gamma-aminobutyric acid (GABA) receptor 
agonist that binds as an orthosteric agonist to the α4- and δ-containing subunit of extrasynaptic 
GABA receptors. Research has shown that absence (or dysfunction) of Ube3a results in an 
aberrant increase in the uptake of GABA, which is the main inhibitory neurotransmitter in the 
brain. The extrasynaptic GABA receptors mediate tonic inhibition and sleep maintenance. In a 
mouse model of AS, OV101 was shown to restore tonic inhibition in Ube3a-deficient cerebellar 
neurons and correct motor abnormalities in Ube3a-deficient mice (Egawa et al 2012). These 
results suggest that OV101 may alleviate the motor dysfunction observed in individuals with AS. 
Importantly, OV101’s ability to potentiate tonic inhibition is unlike any other GABAergic agent, 


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OV101-16-001 (NCT03109756) was a Phase 1, single-dose pharmacokinetic (PK) study in
including benzodiazepines, zolpidem, zaleplon, zopiclone, barbiturates, neurosteroids, and drugs 
that act on GABA metabolism or uptake. Unlike many of these drugs that are allosteric 
modulators and therefore require endogenous GABA to function, OV101 is a GABA agonist and 
can function when GABA is deficient or absent. In addition to the data on presynaptic 
dysfunction leading to reduced tonic inhibition, there are additional studies which speak to the 
potential of OV101 in AS, including modulation of sleep and cognition domains that are 
impaired in subjects with AS (Ramamoorthi and Lin 2011; Brickley and Mody 2012; Egawa and 
Fukuda 2013; Deidda et al 2014; Berry et al 2015; Dissel et al 2015).  
Phase 2 and Phase 3 studies in adult subjects with primary insomnia demonstrated that OV101 is 
effective in restoring classical sleep parameters (sleep induction and sleep maintenance) and 
slow wave sleep, resulting in an improvement in the quality and restorative effects of sleep. 
 
 
 
 
 
 
 
 
 
A randomized, double-blind, placebo-controlled Phase 2 study (OV101-15-001[STARS]; 
NCT02996305) evaluated the safety, tolerability, and exploratory measures of efficacy of OV101 
in adolescents and adults with AS over 12 weeks of treatment. The STARS study was the first 
industry Sponsored clinical study in AS. Overall, OV101 had a favorable safety profile and was 
well tolerated. OV101 had a statistically significant effect on the Clinical Global 
Impressions-Improvement (CGI-I), a measure of global function included as an exploratory 
measure. Exploratory and post-hoc analyses suggested that improvements seen on the CGI-I 
were likely driven by sleep, gross and fine motor function, behavior, and communication. 
 
Eighty-eight subjects with AS (13 to 49 years old) were randomly assigned to 1 of 3 groups: 
once daily (QD) dose of OV101 nightly (15 mg), twice daily (BID) dose of OV101 (10 mg 
morning and 15 mg night), and placebo. The safety and tolerability of OV101 from baseline to 
Week 12 was evaluated by comparing the frequency and severity of adverse events (AEs) and 
serious AEs (SAEs) in the OV101 treatment groups to those in the placebo group. OV101 was 
generally safe and well tolerated, with a similar incidence and severity of AEs across all 
time to Cmax (tmax) was 1.1 hours after dosing.
Maximum plasma concentration (Cmax) of OV101 ranged from 71 to 159 ng/mL, and the mean
detectable from 0.25 hours post-dose until the last PK sampling time point at 10 hours post-dose.
Dosing; Section 3.1.1). In this study, plasma OV101 concentrations after a 5-mg oral dose were
bands to achieve exposures similar to those observed in adolescents and adults (Rationale of
PK (PBPK) model that served to estimate dose levels across various age groups and weight
from adolescents, combined with data from adults, were used to develop a physiologically-based
adolescent subjects (13 to 17 years old, inclusive) with Fragile X syndrome or AS. The PK data


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Subsequent analyses of the Aberrant Behavior Checklist, Anxiety, Depression and Mood Scale,
The MMRM analysis of actigraphy sleep data showed greater decreases in latency of sleep onset
treatment groups: most AEs were mild. Treatment discontinuations due to AEs were low 
(placebo, 1; OV101 QD, 0; OV101 BID, 3). The most frequent AEs across all treatment groups 
were vomiting, somnolence, irritability, aggression, pyrexia, and upper respiratory infection. The 
AEs occurring in the OV101 treatment groups with greater frequency than placebo were pyrexia, 
rash, seizure, enuresis, myoclonic epilepsy, otitis media, and viral infection. Serious adverse 
events of seizure were reported in 2 subjects, both of whom had a previous history of seizures: 1 
subject in the QD dose experienced a seizure and that was deemed unrelated to study drug and 
treatment was continued; 1 subject experienced 2 events of seizure in the BID dose group that 
was assessed as possibly related to study drug by the investigator, and treatment was 
discontinued. Overall, the data are consistent with a favorable risk profile. 
Clinical efficacy measures used to compare OV101 versus placebo during the 12 weeks of 
treatment included the CGI-I, Aberrant Behavior Checklist, Anxiety, Depression and Mood 
Scale, Sleep Diary, and modified Performance-Oriented Mobility Assessment-Gait tool. 
For the CGI-I Symptoms Overall domain at Week 12, the Mixed Model Repeated Measures 
(MMRM) analysis showed a significant improvement for OV101 compared to placebo for the 
OV101 groups combined (P=0.0103) and for the OV101 QD group (P=0.0006). At Week 12, 
subjects in the OV101 QD group showed significant improvement in CGI-I Symptoms Overall 
regardless of age. 
 
For the CGI-I Sleep domain at Week 12, the MMRM analysis showed a significant improvement 
for OV101 compared to placebo for the OV101 groups combined (P=0.0236) and for the OV101 
QD group (P=0.0141).  
 
 
 
 
 
 
 
 
 
 
 
In post hoc analyses at Week 12, most subjects in the OV101 groups combined (54.5%) had 
responses of minimally improved (34.5%) or much improved (20.0%) for CGI-I Symptoms 
worsening in the OV101 BID and placebo groups).
(17.99) minutes in the OV101 BID group and 12.7 (24.07) minutes in the placebo group (i.e.,
LSO in the OV101 QD group was –15.1 (36.64) minutes (i.e., improvement), compared to 1.0
placebo –18.87 minutes, P=0.0276) compared to placebo. Mean (SD) change from baseline in
25.68 minutes, P=0.0147) and in the OV101 groups combined (LS means difference from
(LSO) from baseline to Week 12 in the OV101 QD group (LS means difference from placebo –
statistical separation from placebo for the combined OV101 groups.
and modified Performance-Oriented Mobility Assessment-Gait assessments did not show
Sleep Diary, 


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Overall, compared to 22.2% of subjects in the placebo group (14.8% minimally and 7.4% much 
improved). The percentages of subjects with improvement were larger in the OV101 QD group 
(66.6%; 29.6% minimally, 37.0% much improved) than in the OV101 BID group (42.8%; 32.1% 
minimally, 10.7% much improved). 
 
NEPTUNE (OV101-19-001) will be a multicenter, randomized, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of OV101 in pediatric subjects with AS. 
Subjects who complete the study will be eligible to enroll in the ongoing OV101-18-002 
(ELARA) open-label extension study, provided they meet the eligibility criteria for ELARA. 


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2 
Study Objectives 
All efficacy study objectives will be assessed in the pediatric AS study population of subjects 
who are 4 to 12 years old. All safety study objectives will be assessed in the pediatric AS study 
population of subjects who are 2 to 12 years old. 
2.1 Primary Objective 
x To evaluate the efficacy of OV101 versus placebo as assessed by the Clinical Global 
Impressions-Improvement-Angelman syndrome (CGI-I-AS) score at Week 12. 
2.2 Secondary Objectives 
Key Secondary Objectives: 
The purpose of the key secondary objectives is to fulfil a recommendation of the EMA for a 
responder analysis. 
x To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of subjects 
who experience any meaningful improvement on study treatment (defined as CGI-I-AS 
score of 1, 2, or 3 at Week 12) 
x To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of subjects 
who experience a response of much improved or very much improved (defined as CGI-I- 
AS score of 1 or 2 at Week 12 
Other Secondary Efficacy Objectives: 
x
x To evaluate the efficacy of OV101 versus placebo on Communications, Socialization, 
Daily Living Skills, Motor Skills, and Maladaptive Behavior domains assessed by the 
Vineland Adaptive Behavior Scale, 3rd Edition (VABS-3). 
x To evaluate the efficacy of OV101 versus placebo based on the Clinical Global 
Impressions-Severity-Angelman syndrome (CGI-S-AS) Symptoms Overall score. 
x To evaluate the relationships of CGI-S-AS Symptoms Overall and CGI-S-AS domains at 
baseline with CGI-I-AS at Week 12. 
sleep assessed by actigraphy.
To evaluate the efficacy of OV101 versus placebo on LSO, sleep efficiency, and daytime


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The tertiary efficacy objectives of this study are:
x
assessed by actigraphy.
To evaluate the efficacy of OV101 versus placebo on total sleep time and total activity
x
reported).
To evaluate the efficacy of OV101 versus placebo based on sleep diary data (caregiver
x
Questionnaire (CSHQ).
To evaluate the efficacy of OV101 versus placebo based on the Children’s Sleep Habits
x
modules).
Inventory™(Peds QL™) (Cerebral Palsy, Multidimensional Fatigue, and Family Impact
To evaluate the efficacy of OV101 versus placebo based on the Pediatric Quality of Life 
The PK objectives of this study are to estimate systemic plasma exposure to OV101 (maximum
 
 
 
 
 
 
 
2.4 
 
 
 
 
 
2.5 Safety Objectives 
The safety objectives of this study are to evaluate the safety and tolerability of OV101 in subjects 
2 to 12 years old, including seizure diary data and assessment of suicidality. 
population 2 to 12 years old.
estimated PK parameters in the context of a validated PBPK model for the pediatric study
single oral dose using sparse sampling and a population PK approach as well as to evaluate
plasma concentration [Cmax] and area under the concentration-time curve [AUC]) following a
2.3 Tertiary Objectives
Pharmacokinetic Objectives
x
x
x
x


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3 
Investigational Plan 
3.1 Study Design 
This will be a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study, 
conducted in clinic settings, to evaluate the efficacy and safety of OV101 in pediatric subjects 
with AS. Male and female subjects with a previous diagnosis of AS (with molecular 
confirmation) will be eligible for inclusion (Section 4.1). The study will comprise a screening 
period within the 28 days preceding Day 1; a visit on Day 1 for baseline assessments, the first 
dose of study drug, and sparse sampling of blood; subsequent doses of study drug taken each 
evening approximately 30 minutes before bedtime for 12 weeks starting on Day 2; and study site 
visits for efficacy and safety assessments over a 12-week treatment period. After the baseline 
visit, the study site visits will occur at Week 6 and Week 12 (end of treatment [EOT]). Phone 
safety visits will occur during up-titration of the study drug (Day 6 and Day 11). Unless a subject 
decides to participate in the ELARA open-label extension study, an end of study (EOS) phone 
safety visit will occur approximately 2 weeks after the last dose of study drug to assess safety 
and tolerability associated with discontinuation of treatment. Subjects eligible for and willing to 
enroll in the ELARA study will have the NEPTUNE EOT visit be their NEPTUNE EOS visit, 
and their NEPTUNE EOT visit will serve as their ELARA baseline visit. A subject will be 
considered to have completed the NEPTUNE study after completing the EOS visit. For 
NEPTUNE subjects participating in ELARA, the EOS visit that occurs approximately 2 weeks 
after the EOT will take place in the ELARA study only. The total duration of the study for a 
subject will be approximately 18 weeks. The schedule of activities for this study is fully 
presented in Table 6–1. 
Approximately 95 subjects will be enrolled in the study at approximately 15 study sites in the 
United States, Israel, Australia and/or Europe. Approximately 90 subjects 4 to 12 years old 
(inclusive) will be enrolled for both efficacy and safety assessments, and not more than 12 of 
these subjects will be enrolled at a study site (unless authorized by Sponsor). Random 
assignment of subjects for efficacy assessment (to either OV101 or placebo treatment in a 1:1 
ratio) will be stratified by age at screening [9 to 12 years old (inclusive) and 4 to 8 years old 
(inclusive)] and by region (US and outside US). There will be at least 24 subjects per age group. 
Approximately 5 subjects 2 to 3 years old (inclusive) will be enrolled for safety 
assessments only and will be assigned to treatment with OV101. Within each age group, dosing 
will be assigned based on body weight (Table 5–1). 
For each subject, after informed consent is obtained (Section 9.3), screening assessments will be 
completed within the 28 days preceding Day 1 (baseline). On Day 1, eligible subjects will 
receive study drug capsules according to treatment code (sufficient to last until the Week 6 visit). 
and PBPK


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The PBPK model used to derive dose and exposure levels for the present study was validated
x
4 to 8 years old (inclusive): 8 mg
x
2 to 3 years old (inclusive): 5 mg
x
6 months to less than 2 years old: 4 mg (age group not included in the proposed study)
While the PBPK model yielded dosing information for children from 6 months to 12 years of age
The OV101 AUC0-∞ and Cmax exposure parameters for the above age-based fixed dose levels
Caregivers/LARs will be provided an additional blister card in case of unexpected delays for 
study visits (e.g., inclement weather/flight delays). Study drug will be similarly dispensed at the 
Week 6 visit. Unused study drug will be collected and counted at Week 6 and 12. 
3.1.1 Rationale of Dosing 
 
Timing of dosing, each evening at bedtime, was selected based on the efficacy of evening dosing
in the OV101-15-001 study (Section 1). Selection of the dose for each age group was based on  
PBPK modeling for the pediatric population and data derived from the OV101-16-001 study 
(Section 1; Ovid Therapeutics Inc 2018) and other OV101 PK studies in adults (Merck 2001;
Merck 2006).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3–1.
derived from the PBPK model based upon 1000 virtual subjects per age group are shown in
(below), only subjects between 2 and 12 years of age will be evaluated in this study.
9 to 12 years old (inclusive): 10 mg
x
dose levels are shown below:
regimen yielded dose levels for pediatric subjects age 12 years to 6 months of age. The age-based
adolescents while minimizing the risk of AEs associated with Cmax. This age-based dosing
age, were determined to align overall OV101 exposure (AUC0-∞) with that achieved in adults and
tmax. The following dose levels based upon age, for pediatric subjects 12 years to 6 months of
adolescent subjects are typically associated with Cmax of gaboxadol, with onset occurring around
Cmax, since clinical studies have shown that AEs associated with OV101 in adult, elderly, and
receiving 15 mg) to avoid Cmax-related AEs. Dose levels and regimen simulations focused on
dose of 15 mg, while underexposing in terms of Cmax (approximately 54-63% of that of adults
time curve from 0 to infinite hours [AUC0-∞]) in adults and adolescents receiving a fixed oral
across various pediatric age bands to match the OV101 exposure (area under the concentration-
with both adult and adolescent PK data and was used to establish a fixed-dose level regimen
x
x
x


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mo, month; QD, once daily; SD, single dose; y, year.
Although exposure matching to adults receiving 15 mg of OV101 allowed for dose levels to be
In this weight-based regimen (Table 5–1), older subjects (9 to12 years old) will be dosed first, 
Table 3–2
Fixed Doses of OV101 for Pediatric Subject Body Weight Ranges
Model-Predicted Exposure (AUC0-∞ and Cmax) on Days 1 and 5 After
Dose
Dose
AUC0-∞ 
Cmax
median wt)
0.21
0.23
0.22
474.9
475.5
152.5
151.9
(low wt)
(Day 5)
(Day 1)
(Day 5)
(Day 1)
(mg/kg,
(mg/kg,
Cmax 
AUC0-∞ 
High
Fixed
Dose
68.5
15 
70 
65 
(mg)
high wt)
(kg)
(kg)
(kg)
(mg/kg,
Dose
Wt
Wt
Wt
Median
Low
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The PBPK model was then used to predict AUC0-∞ and Cmax exposure parameters for pediatric
OV101 oral maintenance weight-based dose levels, with 1000 virtual subjects for each weight 
range (Study Report PKPD18-1074.00). Table 3–2 summarizes the predicted weight-based  
maintenance dose exposure parameters on dosing days 1 and 5.  
dose level will be allowed.
maintenance dose not be well-tolerated in any subject, 1 down-titration to a reduced maintenance
to a maintenance dose (approximating a 15-mg equivalent dose in adults). Should the
known to be well-tolerated in more sensitive elderly subjects) for 5 days, followed by up-titration
will first receive a lower starting dose (approximating a 10-mg equivalent dose in adults, a dose
dose groups, with lower doses per kg body weight in the youngest subjects. In addition, children
(Section 5.1). The weight-based maintenance dose levels would be less than 0.23 mg/kg for all
followed by younger subjects if the dose levels given to older children are well tolerated
risk of over- or under-dosing.
a weight-based dosing regimen across the 2- to 12-year-old age range was chosen to reduce the
considerable, with outliers driving the greatest risk of either over- or under-dosing. Accordingly,
estimated for various ages, weight variations in children of various age bands can be
Exposures in Adults Receiving an OV101 Dose of 15 mg
Receiving Predicted Exposure-Matched OV101 Doses vs Observed
Predicted Exposure Parameters in Pediatric Subjects at Various Ages
Table 3–1
Predicted
Ratio
Predicted
Ratio
Predicted
Ratio
Predicted
Ratio
adult
538
458.4
0.85
540.4
1.00
491
0.91
485.6
0.90
389
208.5
0.54
233.5
0.60
220.4
0.57
244.1
0.63
Abbreviations: AUC0-∞, area under the concentration-time curve from 0 to infinite hours; Cmax, maximum plasma concentration; 
(ng/mL)
Cmax 
(ng×h/mL)
AUC0-∞ 
SD
2 y/
4 mg QD
adult
adult
5 mg QD
8 mg QD
adult
10 mg QD
15 mg
6 mo-
2-4 y/
6 mo-2 y
2-4 y
4-8 y/
4-8 y
9-12 y/
9-12 y
Adult
Observed 
Parameter
15 
high wt)
(
g g,
(mg)
70 
(kg)
65
(kg)
(low wt)
(
g g,
(Day 5)
(Day 1)
Abbreviations: AUC0-∞, area under the concentration-time curve from 0 to infinite hours; Cmax, maximum plasma concentration;
SD
4 mg QD
6 mo-2 y
adult
2-4 y/
5 mg QD
y
adult
y
6 mo-


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Overall, simulated OV101 exposures (Cmax and AUC0-∞) produced by maintenance dose levels of
43 
64 
54 
10 
0.16 
0.23 
0.187 
482.8 
483.2 
182.4 
182.3 
 
35 
 
42 
 
39 
 
8 
 
0.19 
 
0.23 
 
0.21 
 
392.2 
 
392.4 
 166.1  165.9 
 
 
 
 
 
 
 
 
 
 
 
 
26 
 
34 
 
30 
 
6 
 
0.18 
 
0.23 
 
0.2  
 
305.6 
 
305.8 
 138.7  138.4 
 
 
 
 
 
 
 
 
 
 
 
17
25
21
4
0.16
0.24
0.19
307.1
306.9
133.4
133
 
 
 
 
 
 
 
 
 
 
 
 
9  
 
16 
 
13 
 
2 
 
0.13 
 
0.22 
 
0.16 
 
197.4 
 
197.2  
91.5   
90.9  
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AUC0-∞, area under the concentration-time curve from 0 to infinite hours; Cmax, maximum plasma concentration;
 
wt, weight.
Note: Units for AUC0-∞ are ng×h/mL and for Cmax are ng/mL.  
Sources: Arithmetic means of model-predicted PK parameters were derived from the following appendices in Study Report  
 
PKPD18-1074.00: Appendices 13, 20, 21, 22, 23, and 24.  
 
 
 
 
 
 
weight band (10 mg).
predicted AUC0-∞ and at most 76% of maximally predicted Cmax levels observed in the 43-64 kg
produces exposure levels in subjects less than 34 kg that are at most 64% of the maximally
the initial age-based dosing bands. It is notable that the proposed dosing based on weight bands 
OV101 across the various weight ranges are similar to or lower than the exposures predicted for
182.3
182.4 
483.2 
482.8 
0.187 
0.23 
0.16 
10 
54 
64 
43 


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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 95 subjects will be enrolled at approximately 15 study sites, with a goal of having 
80 subjects evaluable for efficacy by completing 12 weeks of treatment (Section 3.1). Subjects 
will be assigned to study treatment only if they meet all inclusion criteria and none of the 
exclusion criteria. 
 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, and/or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
 
4.1.1 Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in this study: 
 
1. Is male or female and 2 to 12 years old (inclusive) at the time of informed consent. 
2. Has a diagnosis of AS with molecular confirmation. 
3. Has a CGI-S-AS score (Section 6.2.1.1) of 3 or more. 
4. Meets the following age-appropriate body weight criterion: 
a) Subjects 2 to 3 years old must have a minimum body weight of 9 kg. 
b) Subjects 4 years and older must be between 17 kg and 64 kg (inclusive). 
5. Has an LAR/caregiver capable of providing written informed consent and able to 
attend all scheduled study visits, oversee the administration of study drug, and 
provide feedback regarding the subject’s symptoms and performance as described in 
the protocol. 
6. Provides assent to the protocol (to the extent possible and in accordance with local 
institutional review board [IRB] and regulatory requirements). Subjects providing 
assent must do so at the same visit as LAR/caregiver written informed consent is 
provided. 
7. Can swallow study drug capsules with water or ingest the contents of study drug 
capsules after sprinkling the contents of each capsule onto up to 1 teaspoon of low- 
fat semiliquid food. 


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8. If a subject is currently receiving a regimen of concomitant medications such as 
antiepileptic medication, gabapentin, clonidine, trazodone, melatonin, or a special 
diet regimen, that subject’s regimen is stable for at least 4 weeks before Day 1 (first 
day of study drug administration) and will be maintained throughout the duration of 
the study (in the judgment of the investigator). 
9. If a subject is a sibling in a family with multiple children diagnosed with AS, then 
only one of the siblings may enroll in study. The eldest eligible subject should be 
enrolled (investigator discretion may be used to enroll a younger sibling instead). 
10. Has LAR(s)/caregiver(s) who agree not to post any of the subject’s personal medical 
data or information related to the study on any website, message board(s), online 
support group(s), or social media site (e.g., Facebook, Instagram, Twitter, etc.) until 
notified that the study is completed. 
11. Female subjects who are of child-bearing potential (defined as having experienced 
their first menarche) must agree to use either a highly effective or acceptable form of 
birth control during the study and for 30 days following the last dose of the study. 
Highly effective contraceptive methods are as follows: 
12. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
13. Oral 
14. Intravaginal 
15. Transdermal 
16. Progestogen-only hormonal contraception associated with inhibition of ovulation: 
17. Oral 
18. Injectable 
19. Implantable 
20. Intrauterine device 
21. Intrauterine hormone-releasing system 
22. Bilateral tubal occlusion 
23. Vasectomized partner 
24. Sexual abstinence 


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Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 
 
a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action. 
 
b. Male or female condom with or without spermicide. 
 
c. Cap, diaphragm or sponge with spermicide. 
 
d. A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods) are also considered acceptable, but not 
highly effective, birth control methods 
 
4.1.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
 
1. Has a circumstance or concomitant disease (e.g., gastrointestinal, renal, hepatic, 
endocrine, respiratory, or cardiovascular system disease), condition, or any clinically 
significant finding at screening that could interfere with the conduct of the study or that 
would pose an unacceptable risk to the subject in the opinion of the investigator. 
 
2. Has poorly controlled seizures defined as any of the following: 
 
a. Weekly seizures of any frequency with a duration more than 3 minutes. 
 
b. Weekly seizures occurring more than 3 times per week, each with a duration of 
less than 3 minutes. 
 
c. Investigator assessment. 
 
3. Has any of the following laboratory abnormalities: total bilirubin >1.5 × upper limit of 
normal (ULN), unless known Gilbert’s syndrome; alanine aminotransferase or aspartate 
aminotransferase >2.5 × ULN; serum creatinine >1.2 × ULN; absolute neutrophil count 
<1.5 × 109/L; platelets <80 × 109/L; hemoglobin <80 g/L; or 
thyroid-stimulating-hormone >1.25 × ULN or <0.8 × lower limit of normal. Retesting of 
clinical laboratory parameters may be allowed after consultation with the medical 
monitor or designee. 


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consecutive weekend days) during the 28-day screening period of the study, after 3
4. Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, or 
ramelteon for sleep, or minocycline or levodopa within the 4 weeks prior to Day 1 or 
during the study. Benzodiazepines administered as needed for situational anxiety related 
to occasional procedures or events are permitted, and benzodiazepines are also permitted 
for seizure control.  
 
5. 
 
6. Is at risk of harming self and/or others (based on investigator assessment). 
7. Has enrolled in any interventional clinical study or used any investigational agent or 
device, or has participated in any investigational procedure, within the 30 days before 
screening or does so concurrently with this study. 
8. Is allergic to OV101 or any excipients of study drug. 
9. The subject or LAR/caregiver is unable to comply with study requirements (based on 
investigator assessment). 
10. Is a family member of the investigator and/or study site staff. 
4.2 Discontinuation and Withdrawal of Subjects 
Subjects who discontinue treatment during the study will be encouraged by investigators to 
continue to participate in all scheduled study site visits and assessments, and study data will be 
collected for these subjects per protocol. Study drug administration may be stopped early at the 
discretion of the investigator (or designee) if a subject does not tolerate the dosing regimen. 
Every effort should be made to keep subjects in the study. 
Early withdrawal of a subject from the study (before Week 12) will initiate procedures for ending 
all subject participation in the study, including EOT and EOS assessments (Section 4.2.2). For 
subjects who are withdrawn early, an EOT visit should be conducted within 2 weeks after the last 
day of study drug. After completing the EOT visit, an EOS phone visit should be completed 
within 2 weeks after completing the EOT visit. The duration of the study is defined for each 
subject as the date signed written informed consent is provided through the EOS phone visit. The 
Sponsor may continue to enroll subjects to account for discontinuations, withdrawals, early 
terminations, etc. 
attempts.
Cannot tolerate wearing the actigraph for at least 7 consecutive days (including 2


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4.2.1 Reasons for Withdrawal 
Subjects may withdraw from the study at any time and for any reason without prejudice to their 
future medical care by the investigator or at the study site. The reasons for subjects not 
continuing in the study will be recorded. A subject may be withdrawn from the study for any of 
the following reasons: 
 
1. The subject does not continue to meet the protocol inclusion or exclusion criteria. 
 
2. The subject has a serious or intolerable AE that, in the investigator’s opinion, requires 
withdrawal from the study. 
 
3. The subject has laboratory safety results that reveal clinically significant changes from 
baseline in hematological or biochemical assessments. 
 
4. The subject has symptoms (or an intercurrent illness) that are not consistent with the 
protocol requirements or that justify withdrawal. 
 
5. The subject is lost to follow-up. 
 
6. Other reasons (e.g., development of contraindications to use of study drug). 
 
7. The subject (or his LAR/caregiver) withdraws assent (consent) or the investigator or 
Sponsor decides to discontinue the subject’s participation in the study. 
 
The investigator will also withdraw a subject if the Sponsor terminates the study. Upon 
occurrence of a serious or intolerable AE, the investigator will confer with the medical monitor 
and/or Sponsor. If a subject is discontinued because of an AE, the event will be followed until it 
is resolved. 
 
4.2.2 Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time upon request. Subject 
participation in the study may be stopped at any time at the discretion of the investigator or at the 
request of the Sponsor. 
 
Subjects who stop study treatment or active participation in the study will no longer receive 
study drug. When a subject withdraws from the study treatment or active participation in the 
study, the reason(s) for withdrawal shall be recorded by the investigator on the relevant page of 
the electronic case report form (eCRF) using the electronic data capture (EDC) system. 
Whenever possible, all subjects who stop study treatment or withdraw from the study 


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prematurely will complete the EOT and EOS assessments. Subjects who fail to return for final 
assessments will be contacted by the site (2 documented phone calls followed by 1 registered 
letter, as applicable) in an attempt to have them comply with the protocol. 
 
It is vital to obtain follow-up data on any subject withdrawn or who withdraws because of an AE 
or SAE. In every case, efforts must be made to undertake protocol-specified safety follow-up 
procedures. 
 
4.2.3 Replacements 
A sufficient number of subjects will be enrolled to ensure that at least 80 evaluable subjects (4 to 
12 years old) complete 12 weeks of treatment. 
 
A subject who does not meet the inclusion criterion or who meets an exclusion criterion will be 
considered a screen failure. Whether rescreening is acceptable will be discussed with the medical 
monitor or his designee. Rescreening may be allowed if the subject passed screening but could 
not be randomly assigned within the 28-day screening window due to logistical, personal, or 
other unforeseeable reasons. Rescreening will only be allowed once and only in cases where no 
safety risk is posed to the subject. 
 
If a screening test result (laboratory or any other test) is considered uncertain or abnormal, the 
test may be repeated to confirm the result after approval from the medical monitor. 


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Not more than 12 subjects 4 to 12 years old (inclusive) will be assigned to treatment at a study
At Day 1, subjects 4 to 12 years old who meet all eligibility criteria will be randomly assigned to
At Day 1, Approximately 5 subjects 2 to 3 years old (inclusive) will be assigned to receive 
 
5 
Study Treatments 
5.1 Method of Assigning Subjects to Treatment Groups 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects assigned to OV101 treatment will be assigned a maximum daily dose and titration
schedule based on their weight at the screening visit, according to Table 5–1. If a subject is 
assigned to placebo, the number of capsules per dose will correspond to the number of OV101
capsules for a subject of the same weight.  
OV101. No subject in the 2- to 3-year-old age group will be assigned to placebo treatment. 
with at least 24 subjects per age category. The regions are US and outside US.
block size. The age groups will be 9 to 12 years old (inclusive) and 4 to 8 years old (inclusive),
stratified by age and region according to 2 age groupings and 2 regions, using an appropriate
receive OV101 or matching placebo in a 1:1 allocation ratio. Random assignment will be
the IDMC charter (Section 11.1.1).
align with data previously observed in adults and adolescents. This will be described in detail in 
data in a blinded fashion to evaluate whether these individual values within each time window
continues during the review). The IDMC will examine the plasma OV101 concentration-time
subjects 2 to 3 years old may begin treatment (initiation of treatment in the 4 to 8 age group
following IDMC review and approval of the tolerability in the sentry subjects 4 to 8 years old,
initiation of treatment in the 9 to 12 age group continuing during the review). Similarly,
tolerability and PK acceptable, subjects 4 to 8 years old (at screening) may begin treatment (with
dose, will be forwarded to the IDMC for review as blinded data. If the IDMC considers the
tolerability assessment of the sentry subjects at Day 11, 5 days after initiation of the maintenance
IDMC review of tolerability and PK in sentry subjects in the previous older cohort. The
these subjects will be termed “sentry subjects.” No age cohort may begin treatment without
will be used to collect at least 3 evaluable OV101 PK samples in each efficacy age group and
12 years old (at screening) will begin treatment first. Initial enrollment of randomized subjects
stratified and staged by age and region and gated by an IDMC (Section 6.5). Subjects 9 to
site (unless authorized by Sponsor), and subject assignment to and initiation of treatment will be


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Band 
Weight Range 
at Screening 
Visit 
(kg) 
Starting Dose 
(mg [capsules]) 
Maint Dose 
(mg [capsules]) 
Maint Dose 
(mg/kg) 
1 
45-64 
6 mg (3× 2 mg) 
10 mg (5× 2 mg) 
0.222–0.156
2 
35-44 
4 mg (2× 2 mg) 
8 mg (4× 2 mg) 
0.23–0.19 
3 
25-34 
2 mg (1× 2 mg) 
6 mg (3× 2 mg) 
0.24–0.176 
4 
17-24 
2 mg (1× 2 mg) 
4 mg (2× 2 mg) 
0.23–0.16 
5 
9-16a 
1 mg (2× 0.5 mg) 
2 mg (4× 0.5 mg) 
0.23–0.125 
 
 
 
An interactive web response system will be used to administer the randomization schedule. The 
PROMETRIKA biostatistics group will generate the randomization schedule using SAS® 
software (SAS Institute Inc, Cary, NC) Version 9.3 or later, which will link sequential subject 
randomization numbers to treatment codes.  
 
5.2 Treatment Administration 
Subjects will take all doses orally each evening (assisted by an LAR/caregiver, if necessary), at 
approximately the same time, approximately 30 minutes before anticipated bedtime, for the 
duration of the 12-week treatment period. Capsules may be opened, with the contents of each 
capsule sprinkled onto up to 1 teaspoon of low-fat semiliquid food (e.g., applesauce, yogurt, 
pudding) for ingestion, but this approach must be followed consistently throughout the study. 
The capsule contents must not be placed directly in liquid. The LAR/caregiver must document 
how capsules were taken (i.e., swallowed whole with water or opened with the contents of each 
capsule taken in up to 1 teaspoon of semiliquid food). 
 
On Day 1, subjects will take their first dose of study drug at the study site during the daytime, 
taking all subsequent doses at night, starting with the evening of Day 2. The LAR/caregiver 
should make every effort to administer the drug at approximately the same time each night. 
 
If a subject misses a dose of study drug for any reason, unless within a 3-hour window of the 
usual administration time, the subject should not make up the missed dose. The subject should 
wait to take the next dose as scheduled and take a single dose at that time. It is important that the 
dosing regimen be documented in the medication diary by the LAR/caregiver and monitored by 
the study site to ensure that appropriate dosing is being followed. Subjects experiencing dose 
interruptions should be evaluated by the investigator in conjunction with the medical monitor. 
Abbreviation: Maint, maintenance.
a
Must be <4 years of age at screening visit.
Daily Dosing and Titration of OV101 by Weight
Table 5–1
PROMETRIKA b
Must be <4 years of age at screening visit.
a
Abbreviation: Maint, maintenance.
0.23–0.125
0.23–0.16
0.24–0.176
0.23–0.19 
0.222–0.156
2 mg (4× 0.5 mg)
4 mg (2× 2 mg) 
6 mg (3× 2 mg) 
8 mg (4× 2 mg) 
10 mg (5× 2 mg) 
1 mg (2× 0.5 mg) 
2 mg (1× 2 mg) 
2 mg (1× 2 mg) 
4 mg (2× 2 mg) 
6 mg (3× 2 mg) 
9-16a
17-24 
25-34 
35-44 
45-64 
Weight Range
at Screening
Visit 
(kg)
5
4
3
2
1
Maint Dose
(mg/kg) 
Maint Dose
(mg [capsules])
Starting Dose 
(mg [capsules])
Band 


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The subject’s maintenance dose for the duration of the study will be set based on the subject’s
If tolerability is not acceptable (e.g., excessive somnolence, dizziness, vomiting, or change in
5.2.1 Dose Titration 
Dosing will be initiated at the starting dose (Table 5–1) for the first 5 days. On Day 6, tolerability 
will be assessed by the investigator. If there are no tolerability concerns (e.g., excessive 
somnolence, dizziness, vomiting, negative behavior changes) and no AE related to the study drug 
has been observed since Day 1 by the LAR/caregiver or the investigator, then the dose of OV101 
will be increased to the maintenance dose for the duration of the study. If tolerability concerns 
are observed on Day 6, the subject will discontinue study drug. Time windows for titrations and 
safety phone visits are presented in Table 6–1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
document.
supporting rationale must be documented in the medical record or other appropriate source
treatment. Any dose adjustments or changes in dosing must be documented in the eCRF and
If a subject cannot tolerate the reduced maintenance dose, that subject must discontinue
dose may not be lower for any subject than the reduced maintenance dose indicated in Table 5–2.
at any time to confirm tolerability. Any intolerability must be documented as an AE. The daily
situation with the medical monitor or his/her delegate. Unscheduled study site visits are optional 
behavior) -at any time during the 12 weeks of treatment, the investigator should discuss the
changes in dose regimen should be made after Day 15.
tolerability with the modified dose regimen within 3 days of the dosing change. No further
AEs, or medical necessity. If down-titration is initiated, then the investigator should reassess
on Day 11 by 1 capsule (Table 5–2) based on the investigator assessments of tolerability and
call while the subject is taking the maintenance dose. The investigator may initiate down-titration
the Day 6 assessment until the EOS. Tolerability will again be assessed during the Day 11 phone
weight at the screening visit, and the subject should continue taking the maintenance dose after


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Yourway Transport
Transport
OV101 will be formulated as the monohydrate form of gaboxadol (4,5,6,7-tetrahydro-
 
 
Band 
Weight 
Range at 
Screening 
Visit 
(kg) 
Maint Dose 
(mg [capsules]) 
Maint Dose 
(mg/kg) 
Reduceda Maint 
Dose 
(mg [capsules]) 
Reduceda 
Maint Dose 
(mg/kg) 
1 
45-64 
10 mg (5× 2 mg) 
0.222–0.156 
8 mg (4× 2 mg) 
0.177–0.125
2 
35-44 
8 mg (4× 2 mg) 
0.23–0.19 
6 mg (3× 2 mg) 
0.172–0.136
3 
25-34 
6 mg (3× 2 mg) 
0.24–0.176 
4 mg (2× 2 mg) 
0.16–0.118 
4 
17-24 
4 mg (2× 2 mg) 
0.23–0.16 
2 mg (1× 2 mg) 
0.118–0.08 
5 
9-16b 
2 mg (4× 0.5 mg) 
0.23–0.125 
1.5 mg (3× 0.5 mg) 
0.167–0.09 
 
 
The study site will document each titration step in the eCRF and in source documents. AEs 
triggering any down titration must be reported.  
5.3 Identity of Investigational Product 
 
 
 
 
Placebo capsules will be identical in appearance to the capsules containing OV101 and have the 
same excipient ingredients but will not contain the active compound.  
 
Metrics Contract Services (Greenville, NC) will manufacture the OV101 and placebo capsules. 
 
5.4 Management of Clinical Supplies 
Bulk capsules of OV101 will be shipped to 
will package and label kits. 
 
 
 
will ship the kits directly to each study 
site. 
 
5.4.1 Study Drug Packaging and Storage 
 
Study drug will be supplied as capsules on blister cards for subjects 4 to 12 years old. A clinical 
label will be affixed to the outside of each card. The label will specify the Sponsor name (Ovid 
Therapeutics Inc.); subject number; protocol number; card number; number of capsules (each  
card); “Evening,” and “Take as directed.” Cards will be dispensed at Day 1 and at the Week 6
visit. The recommended storage conditions and expiry date (where required) will be stated on the
microcrystalline cellulose and magnesium stearate.
0.5-mg strengths (of the anhydrous free zwitterion equivalent). Excipients will be
isoxazolo[5,4-c]-pyridin-3-ol, monohydrate) in white size 2 hard gelatin capsules, in 2-mg and
Abbreviation: Maint, maintenance.
a
b
The reduced dose results from a down-titration, 1 capsule less per day.
Must be <4 years of age at screening visit.
Down-Titration of OV101 by Weight
Table 5–2
Yourway Transport (Allentown, PA). Yourway
Metrics Contract Services (Greenville, NC) w
Must be <4 years of age at screening visit.
The reduced dose results from a down-titration, 1 capsule less per day.
a
Abbreviation: Maint, maintenance.
b
0.167–0.09
0.118–0.08
0.16–0.118
0.172–0.136
0.177–0.125
1.5 mg (3× 0.5 mg) 
2 mg (1× 2 mg) 
4 mg (2× 2 mg) 
6 mg (3× 2 mg) 
8 mg (4× 2 mg) 
0.23–0.125
0.23–0.16 
0.24–0.176 
0.23–0.19 
0.222–0.156 
2 mg (4× 0.5 mg) 
4 mg (2× 2 mg) 
6 mg (3× 2 mg) 
8 mg (4× 2 mg) 
10 mg (5× 2 mg) 
9-16b
17-24 
25-34 
35-44 
45-64 
Visit
(kg)
Range at
Screening
Weight 
g
5 
4 
3 
2 
1 
Maint Dose
(mg/kg) 
Reduceda
Dose
(mg [capsules])
Reduceda Maint 
a
Maint Dose
(mg/kg)
(mg [capsules])
Maint Dose
Band 


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Subjects 2 to 3 years old will be supplied with study drug capsules in bottles, to be labeled and
Subjects and LARs/caregivers must be instructed to keep all study drug in the original cards and
Actigraphs (Section 6.2.2) will be supplied to study sites and managed throughout the study as
 
 
 
 
 
 
 
 
5.4.2 Test Article Accountability 
The investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study drug is 
dispensed and used by each subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all study drug will be reconciled and retained or 
destroyed according to applicable regulations.  
 
5.4.3 
 
 
 
5.5 Overdose Management 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in the protocol. Any overdose, with or without associated AEs, must be 
recorded in the eCRF. Any AEs associated with an overdose should be reported on relevant 
AE/SAE sections in the eCRF. Any associated SAEs must be promptly reported to Ovid using 
the SAE reporting procedures (Section 6.4.1.5). Overdoses without signs or symptoms do not 
need to be recorded as AEs. 
 
5.5.1 Treatment of Overdose 
In the event of a suspected overdose, the appropriate supportive clinical care should be provided 
as dictated by the subject’s clinical status. 
 
5.5.2 Medication Errors 
A medication diary will be maintained by the LAR/caregiver on behalf of the subject for the 
duration of the treatment period to confirm dosing dates and times and to permit monitoring for 
described in the study manual.
maintain the cards at room temperature.
stored as described for blister cards.
to 25°C).
cabinet), protected from moisture, and kept at a controlled room temperature, 59°F to 77°F (15°C
product label. At the study site, study drug must be stored in a secure area (e.g., a locked
Other Supplies


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medication compliance and medication errors. The medication diary will be reviewed at the 
Week 6 and Week 12 clinic visits by either the site investigator or the study coordinator. If a dose 
is missed, this should be noted, and the dose should not be doubled at the next scheduled dose. 
 
5.5.3 Treatment of Medication Errors 
An example of a medication error includes overdose (treatment of overdose is described in 
Section 5.5.1). 
 
5.6 Blinding 
The study will be performed in a double-blind manner for subjects 4 to 12 years old (inclusive), 
with the subjects, LAR/caregivers, investigators, study personnel, monitors, and study Sponsor 
blinded to the identity of all study drug. All study drug will be supplied in identical packaging 
and will be similar in color, smell, taste, and appearance to enable double-blind conditions. 
Titrations will be conducted identically for all subjects in a weight band (Table 5–1), regardless 
of assignment to OV101 or placebo. 
 
The study will not be blinded for subjects 2 to 3 years old, inclusive. 
 
5.6.1 Breaking the Blind 
A subject’s treatment assignment will not be broken until after the last subject has completed the 
study and the database has been locked, unless medical treatment of the subject depends on 
knowing the study treatment the subject received. If the blind needs to be broken because of a 
medical emergency where medical management depends on knowing treatment allocation, the 
investigator may unblind an individual subject’s treatment allocation. Before unblinding a 
subject’s treatment assignment and as soon as possible, the investigator should make every effort 
to contact the medical monitor to discuss the medical emergency and the reason for revealing the 
treatment received by that subject. The treatment assignment will be unblinded through an 
interactive web response system. Reasons for treatment unblinding must be clearly explained and 
justified in the eCRF. The date on which the code was broken and the identity of the person 
responsible must also be documented. If a subject’s treatment is unblinded, the Sponsor must be 
notified immediately. Unblinding should only be considered for the safety of the subject. The 
investigator should inform the Sponsor that the subject was unblinded; however, they are not 
required to reveal to the Sponsor the subject’s treatment allocation. 
 
When an AE is an unexpected related SAE, the blind will be broken by the Sponsor only for that 
specific subject. The blind will be maintained for persons responsible for the ongoing conduct of 
the study (e.g., monitors, investigators) and those responsible for data analysis and interpretation 


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of results at the conclusion of the study, such as biometrics personnel. Unblinded information 
will only be accessible to those who need to be involved in the safety reporting to health 
authorities, independent ethics committees (IECs), or IRBs. Investigators will receive only 
blinded information unless unblinded information is judged necessary for safety reasons. 
 
The IDMC (Section 11.1.1) will have the ability to review unblinded data as needed to evaluate 
risk during the study. 
 
5.7 Treatment Compliance 
Subject compliance will be determined by comparing the capsule counts of returned study drug 
cards at the Week 6 and Week 12/EOT visits to the capsule count of study drug dispensed at the 
previous visit. The number of capsules remaining will be tracked and recorded. The 
LAR/caregiver will be questioned as to the reason(s) why unexpected remaining capsules have 
not been administered (e.g., forgot, subject refused, subject experienced AE or LAR/caregiver 
decided to reduce dose), the reason(s) will be recorded, and the approximate date and time of any 
missed doses will be also be recorded in the eCRF. 
 
5.8 Prior and Concomitant Therapy 
Subjects should be on stable doses of prescribed medications and on stable nonmedication 
interventions (e.g., speech therapy, physical therapy, occupational therapy) for 4 weeks before 
Day 1 and should remain on the stable regimens until after the EOS visit. If subjects are to enroll 
in the ELARA open-label extension study, study drug will be provided so that the baseline visit 
can be conducted in conjunction with the NEPTUNE EOT visit. Additionally, unless required to 
treat AEs, there should be no new medications or changes to concomitant medications, approved 
dietary and herbal supplements, and nonmedication interventions during the study until after the 
EOS visit. 
 
Use of all concomitant medications will be recorded in the subject’s eCRF. The minimum 
requirement is that the drug name and the dates of administration are recorded. Concomitant 
medications include all prescription drugs, herbal products, vitamins, minerals, and 
over-the-counter medications. Any changes in concomitant medications will also be recorded in 
the subject’s eCRF. 
 
Any concomitant medication deemed necessary for the welfare of the subject during the study 
may be given at the discretion of the investigator. However, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded in full in the eCRF. 


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5.8.1 Prohibited Medications and Therapies 
Use of any GABAergic agents (e.g., acamprosate, baclofen, vigabatrin, tiagabine, riluzole, and 
gabapentin) on a regular schedule is prohibited from the time informed consent is obtained to the 
end of a subject’s participation in the study. Subjects who entered the study on a stable dose of 
gabapentin (i.e. stable dose for at least 4 weeks prior to randomization), may continue on the 
treatment as long as no dose modifications are expected during the study. Any change in 
gabapentin dose during the study must be captured and documented as a protocol deviation. 
 
Use of benzodiazepines, zolpidem, zaleplon, zopiclone, eszopiclone, barbiturates, or ramelteon 
for sleep is prohibited within the 4 weeks prior to Day 1 or during the study. Benzodiazepines 
administered as needed for situational anxiety related to occasional procedures or events are 
permitted, and benzodiazepines are also permitted for seizure control. 
 
Minocycline and levodopa are prohibited from 4 weeks prior to Day 1 to the end of a subject’s 
participation in the study 
 
Use of other investigational agents is prohibited during the study. 
 
5.8.2 Restrictions 
Any concomitant medication, including antiepileptic and/or behavioral medications, 
supplements, or special diets, must be at a stable dose for at least 4 weeks before Day 1 and must 
be maintained throughout the duration of the study. 
 
Benzodiazepines administered as needed for situational anxiety (e.g., for occasional procedures 
or events) are permitted, as are benzodiazepines for seizure control. 


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The schedule of activities by clinic visit for this study is presented in Table 6–1. Detailed instructions for the conduct of study
assessments and procedures will be provided in the study manual. 
Table 6–1
Schedule of Activities
6 
Study Assessments and Procedures 
 
 
 
Visit Name 
Screening 
Baseline 
 
Phone/  
Week 6 
 
 EOT/  
EOS Phone/ 
Titration
 Week 12  
 
Week 14  
 
Window  
D –28 to D –1  
 
 
+1 Day  
 
±3 Days  
+3 Days  
 
±2 Days  
 
Day  
 
Day 1  
 Days 6 and 11   
Day 43  
 
Day 85  
 
Day 99  
Event  
 
 
 
 
 
 
Informed consent and assenta  
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
Xb 
 
 
 
 
Medical history 
X 
 
Xb,c  
 
 
 
 
Clinical assessmentd for AS
X 
Xb,c
X 
X 
X 
X 
Molecular AS teste  
X
 
 
 
 
 
Dose titration  
 
 
Xf 
 
 
 
Physical examination
X 
Xb,c
X 
X 
Vital signs  
X
Xb 
 
X
X
 
Clinical laboratory tests  
X 
 
Xb,c  
 
X 
X 
 
Adverse events 
X 
Xb 
X 
X 
X 
X 
Concomitant medications  
X 
 
Xb,c  
X 
X 
X 
X 
Assessment of suicidality: ABC-Im  
X 
X 
X 
X 
X 
X 
Seizure diary issued  
X 
X 
 
X 
 
 
Seizure diary collected and reviewed,  
 
X 
 
X 
X 
 
SIF/DRF forms completed/submitted l
Sleep diary issued  
X 
X 
 
X 
 
 
Sleep diary collectedg  
 
X 
 
X 
X 
 
 
Page 56 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb 
X
Xb 
X
Xf 
X
X
X
X
X
X
X
X
X
X
Xb 
X
Week 6 
Baseline
Screening 
Visit Name 
EOS Phone/ 
assessments and procedures will be provided in the study manual.
The schedule of activities by clinic visit for this study is presented in Table 6–1. Detailed instructions for the conduct of study


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Page 57
 
Visit Name
Screening 
Baseline
Phone/ 
Titration 
Week 6
EOT/ 
Week 12 
EOS Phone/ 
Week 14 
Window
D –28 to D –1 
 
+1 Day 
±3 Days
+3 Days 
±2 Days 
Day  
Day 1 
Days 6 and 11 
Day 43
Day 85 
Day 99 
Event 
 
 
 
 
 
Actigraph issuedh 
X 
Actigraph collected 
 
 
 
 
X 
 
Dispense study drug 
 
X 
 
X 
 
 
Collect unused study drug 
 
 
 
X 
X 
 
Review medication diary 
 
 
 
X 
X 
 
PK samplingi 
 
X 
 
 
 
 
CGI-S-AS 
X 
Xb 
 
X 
X 
 
CGI-I-ASj 
 
 
 
X 
X 
 
VABS-3k 
 
X 
 
 
X 
 
Children’s Sleep Habits Questionnaire 
 
X 
 
X 
X 
 
Pediatric Quality of Life Inventory 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ABC-I, Aberrant Behavior Checklist-Irritability subscale; AS, Angelman syndrome; CGI-I-AS, Clinical Global Impressions-Improvement 
Angelman syndrome; CGI-S-AS, Clinical Global Impression-Severity Angelman syndrome; D, day(s); EOS, end of study; EOT, end of treatment; PK, 
pharmacokinetic; VABS-3, Vineland Adaptive Behavior Scale, 3rd Edition. 
Notes: Phone visits may take the form of a video phone call. For subjects completing the study per protocol, the Week 12 visit will be the EOT, and the EOS 
phone visit will occur at Week 14. For subjects discontinuing treatment before Week 12, the EOT visit will occur within 2 weeks after discontinuing 
treatment, and the EOS phone visit will occur 2 weeks after the EOT visit.
a
b
There will be separate informed consent and assent forms for the caregivers and subjects, respectively. 
Baseline visit assessment that must be completed prior to administration of study drug on Day 1.
Day 99
±2 Days
+3 Days 
Week 12
Phone/ 
Titration 
Actigraph issuedh
d
Event
Baseline visit assessment that must be completed prior to administration of study drug on Day 1.
There will be separate informed consent and assent forms for the caregivers and subjects, respectively.
Notes: Phone visits may take the form of a video phone call. For subjects completing the study per protocol, the Week 12 visit will be the EOT, and the EOS
phone visit will occur at Week 14. For subjects discontinuing treatment before Week 12, the EOT visit will occur within 2 weeks after discontinuing
treatment, and the EOS phone visit will occur 2 weeks after the EOT visit.
X
X
X
VABS-3k
CGI-I-ASjS
Xb 
X
Review medication diary 
X
X
Dispense study drug 
Actigraph collected 
b
a
Abbreviations: ABC-I, Aberrant Behavior Checklist-Irritability subscale; AS, Angelman syndrome; CGI-I-AS, Clinical Global Impressions-Improvement 
Angelman syndrome; CGI-S-AS, Clinical Global Impression-Severity Angelman syndrome; D, day(s); EOS, end of study; EOT, end of treatment; P
; VABS-3, Vineland Adaptive Behavior Scale, 3rd Edition.
d
X
X
X
X
X
X
CGI-S-AS 
X
X
X
Collect unused study drug 
X
Day 85 
Day 43
Days 6 and 11
Day 1 
Day
±3 Days
+1 Day 
D –28 to D –1
Window
EOS Phone/ 
Week 14
Week 6
Baseline
Screening 
Visit Name
EOT/ 
g
y
pharmacokinetic;
PK,
X
Pediatric Quality of Life Inventory 
X
X
Children’s Sleep Habits Questionnaire
X
PK samplingi
X
X


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c 
If the screening and baseline visits can be completed within 14 days, the following assessments do not need to be repeated at the baseline visit: medical 
history, clinical assessment, physical examination, clinical laboratory tests, and determination of concomitant medications. Female subjects who have 
experienced menarche will undergo serum beta-human chorionic gonadotrophin pregnancy testing. 
d 
Signs and symptoms of AS. 
e 
Only required if no written evidence for molecular diagnosis is available in the subject records. 
f  Down-titration may be initiated on Day 11 by 1 capsule based on the Investigator’s assessments of tolerability and adverse events, or medical necessity. If 
down-titration is initiated, then the investigator should reassess tolerability with the modified dose regimen within 3 days of the dosing change. No further 
changes in dose regimen should be made after Day 15. 
g  Caregivers will complete sleep diaries on behalf of subjects during the days the subject is wearing the actigraph. Study site staff will call LAR/caregivers to 
remind them when to start recording data in the sleep diary. 
h  An actigraph must be issued to each subject at the screening visit, so that actigraphy data can be collected for 7 days (3 attempts within the 28-day screening 
period are allowed) before the baseline visit. 
i 
At baseline, sampling of blood for determination of concentrations of OV101 will occur 45 minutes ± 15 minutes, 90 minutes ± 15 minutes, and 4 hours ± 
30 minutes after dosing at the study site. Subjects will take all subsequent doses approximately 30 minutes before anticipated bedtime, starting with the 
evening of Day 2 Study site staff will record the time of dosing and the times of blood sampling after the initial dose. 
j 
 Within 24 hours prior to the subject’s visit at Week 6, the investigator must review the subject’s baseline CGI-S-AS score and investigator notes. Within 24 
hours prior to the subject’s visit at Week 12, the investigator must review the subject’s baseline CGI-S-AS score and investigator notes and the Week 6 
CGI-I-AS score and investigator notes. The same clinician rater, trained in CGI-S-AS and CGI-I-AS rating by the Sponsor, must be used throughout the 
study to assess a given subject. It is recommended that the same rater be used at a given site. As an exception, a clinician sub-investigator, trained in 
CGI-S-AS and CGI-I-AS rating by the Sponsor, may be used. 
k 
The VABS-3 will be assessed by a trained qualified rater based on an interview of the subject’s caregiver. For each study site, the same rater is to be used 
throughout the study. As an exception, another Sponsor-trained qualified rater in VABS-3 may be used 
lA Seizure Identification Form and Diagnostic Review Form (SIF/DRF) will be completed by site personnel for every eligible subject. This information will be 
faxed or emailed to The Epilepsy Study Consortium (TESC) for review and approval. The SIF/DRF will be used to ensure that the seizures are classified 
accurately. SIF and DRF forms will be collected for patients who have enrolled/completed the study if feasible. 
m 
The entire Aberrant Behavior Checklist – Community (ABC-C) will be administered. Only ABC-I will be used to evaluate the potential for self-harm 
lA Seizure Identification Form and Diagnostic Review Form (SIF/DRF) will be completed by site personnel for every eligible subject. This information will be
faxed or emailed to The Epilepsy Study Consortium (TESC) for review and approval. The SIF/DRF will be used to ensure that the seizures are classified 
accurately. SIF and DRF forms will be collected for patients who have enrolled/completed the study if feasible.
The entire Aberrant Behavior Checklist – Community (ABC-C) will be administered. Only ABC-I will be used to evaluate the potential for self-harm 
m
The VABS-3 will be assessed by a trained qualified rater based on an interview of the subject’s caregiver. For each study site, the same rater is to be used
throughout the study. As an exception, another Sponsor-trained qualified rater in VABS-3 may be used
k
 Within 24 hours prior to the subject’s visit at Week 6, the investigator must review the subject’s baseline CGI-S-AS score and investigator notes. Within 24
hours prior to the subject’s visit at Week 12, the investigator must review the subject’s baseline CGI-S-AS score and investigator notes and the Week 6
CGI-I-AS score and investigator notes. The same clinician rater, trained in CGI-S-AS and CGI-I-AS rating by the Sponsor, must be used throughout the
study to assess a given subject. It is recommended that the same rater be used at a given site. As an exception, a clinician sub-investigator, trained in
CGI-S-AS and CGI-I-AS rating by the Sponsor, may be used.
j
i
.
h
g
f
Only required if no written evidence for molecular diagnosis is available in the subject records.
e
Signs and symptoms of AS.
d
If the screening and baseline visits can be completed within 14 days, the following assessments do not need to be repeated at the baseline visit: medical
history, clinical assessment, physical examination, clinical laboratory tests, and determination of concomitant medications. Female subjects who have
experienced menarche will undergo serum beta-human chorionic gonadotrophin pregnancy testing.
c
At baseline, sampling of blood for determination of concentrations of OV101 will occur 45 minutes ± 15 minutes, 90 minutes ± 15 minutes, and 4 hours ±
30 minutes after dosing at the study site. Subjects will take all subsequent doses approximately 30 minutes before anticipated bedtime, starting with the
evening of Day 2 Study site staff will record the time of dosing and the times of blood sampling after the initial dose.
An actigraph must be issued to each subject at the screening visit, so that actigraphy data can be collected for 7 days (3 attempts within the 28-day screening
period are allowed) before the baseline visit.
Caregivers will complete sleep diaries on behalf of subjects during the days the subject is wearing the actigraph. Study site staff will call LAR/caregivers to
remind them when to start recording data in the sleep diary.
Down-titration may be initiated on Day 11 by 1 capsule based on the Investigator’s assessments of tolerability and adverse events, or medical necessity. If 
down-titration is initiated, then the investigator should reassess tolerability with the modified dose regimen within 3 days of the dosing change. No further 
changes in dose regimen should be made after Day 15.


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6.1 Screening Assessments 
Screening assessments, used only for determining eligibility for the study or establishing a 
baseline medical history, include confirmation of the molecular diagnosis of AS. 
 
6.2 Efficacy Assessments 
Efficacy assessments will be conducted only for patients in the 4 to 12 year age groups according 
to the schedule presented in Table 6–1. 
 
6.2.1 Efficacy Assessments 
Detailed instructions for the conduct of study assessments and procedures will be provided in the 
study manual. 
 
6.2.1.1 
Clinical Global Impressions Scales 
The CGI-S-AS scale with AS-specific anchors will be used by the investigator to assess the 
severity of symptoms, and the CGI-I-AS scale will be used by investigators to assess 
improvement from baseline. The CGI-S-AS captures specific characteristics commonly present 
in the AS population; the CGI-I-AS captures clinical impression that reflects the rater’s estimate 
of change from the initiation (baseline) of treatment. Both the CGI-S-AS and the CGI-I-AS 
assessments will be conducted by a rater with experience in AS and trained in CGI-S-AS and 
CGI-I-AS rating by the Sponsor. It is recommended that each site uses the same rater. The same 
rater (the principal investigator) at each site must evaluate a given subject throughout the study. 
As an exception, a clinician sub-investigator, trained in CGI-S-AS and CGI-I-AS rating by the 
Sponsor, may be used. The baseline CGI-S-AS will be accompanied by detailed investigator 
notes. Each subsequent CGI-I-AS rating (at Week 6 and Week 12 visits) will also be 
accompanied by detailed investigator notes. To reduce recall bias, within 24 hours before the 
Week 6 CGI-I-AS rating, the rater will review the CGI-S-AS rating and investigator notes from 
the baseline visit. Similarly, within 24 hours before the Week 12 CGI-I-AS rating, the rater will 
review the CGI-S-AS ratings and investigator notes from the baseline visit and from Week 6. If 
the CGI-I-AS assessment is missing at Week 6 or Week 12, the reason for the absence will be 
noted on the eCRF. 
 
6.2.1.2 
Vineland Adaptive Behavior Scale, 3rd Edition 
The VABS-3 is a standardized psychometric instrument designed to measure personal and social 
skills needed for everyday living (Sparrow et al 2005; Sparrow et al 2016). The VABS-3 is 
administered via a caregiver using a semi-structured interview format and assesses 4 main 


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The CSHQ is a retrospective, 33-item caregiver questionnaire that has been used in studies to
The Peds QL Cerebral Palsy, Multidimensional Fatigue, and Family Impact modules will be
adaptive domains: communication (receptive, expressive and written), socialization 
(interpersonal relationships, play and leisure, coping skills), daily living skills (personal, 
domestic, community), and motor skills (fine and gross). It also includes a maladaptive behavior 
scale for identifying behavior problems in children through 18 years of age. The scale has been 
found to have good internal consistency, test-retest reliability and validity (Sparrow et al 2016). 
The VABS-3 interview form will be used to evaluate subjects on the communication, 
socialization, daily living skills, motor skills and maladaptive behavior domains to assess their 
overall functioning. This assessment is an interview of the caregiver by a trained qualified rater, 
and for each study site, the same rater is to be used throughout the study. As an exception, 
another Sponsor-trained qualified rater in VABS-3 may be used. 
6.2.1.3 
 
 
 
 
 
 
 
 
 
 
 
6.2.1.4 
 
 
 
 
 
 
 
 
 
and family relationships.
functioning, communication, and worry. It also assesses caregiver-reported family daily activities
including caregiver-reported assessments of physical, emotional, social, and cognitive
module assesses the impact of pediatric chronic health conditions on caregivers and family, 
assesses general fatigue, sleep/rest fatigue, and cognitive fatigue. The 36-item Family Impact
eating activities, and speech and communication. The 18-item Multidimensional Fatigue module
module assesses daily activities, school activities, movement and balance, pain and hurt, fatigue,
administered in this study (Varni et al 2004; Varni et al 2005). The 22-item Cerebral Palsy
consistently make a higher score indicative of more disturbed sleep.
times/week; and “rarely” for 0 to 1 time/week. The scoring of some items can be reversed to
scale: “usually” if the sleep behavior occurred 5 to 7 times/week; “sometimes” for 2 to 4
immediately preceding the baseline, Week 6, and Week 12 visits. Items are rated on a 3-point
sleepiness. Caregivers will be asked to recall sleep behaviors occurring over the 7 days
night wakings, parasomnias, sleep-disordered breathing, and morning waking/daytime
resistance, sleep-onset delay, sleep duration, anxiety around sleep, behavior occurring around
evaluating the child’s sleep based on sleep behaviors within 8 different subscales: bedtime
to sleep domains that encompass the major presenting sleep complaints in this age group,
examine sleep behavior in young children (Owens et al 2000). The CSHQ includes items relating
Pediatric Quality of Life Inventory
Children’s Sleep Habits Questionnaire


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Actigraphy is a noninvasive method of monitoring human rest/activity cycles. A small wearable
Each subject will be provided a wearable 510(k)-approved actigraph, preferably to be worn on
An actigraph will be issued to each subject at the screening visit, so that actigraphy data can be
6.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.3 
 
A sleep diary will be completed by each subject’s LAR/caregiver, on behalf of the subject.  
Endpoints assessed by the sleep diary are presented in Section 7.2.1.3. The sleep diary will be
completed each day during the days the subject is wearing the actigraph preceding study site 
visits at baseline, Week 6, and Week 12.  
will collect the actigraph.
be given an actigraph to be worn for 7 days after Week 6. At the Week 12 visit, study site staff
consecutive days (including 2 consecutive weekend days) after the Week 6 visit, the subject will 
of continuous use). If the subject requires an additional attempt to keep the actigraph on for 7
data including 2 consecutive weekend days (it is recommended to charge the device after 7 days 
scheduled study site visits at Week 6 and Week 12 visits to collect at least 7 consecutive days of
travel days. The actigraph it is to be worn for a maximum of 14 days preceding travel for the 
These 7 consecutive days should include 2 consecutive weekend days and should not include any
includes 2 weekend days during screening will be used as the baseline actigraphy assessment.
consecutive days. Actigraphy data collected during the first 7-consecutive day period that
days, and subjects will be excluded after 3 unsuccessful attempts to wear the actigraph for 7
attempts within the 28-day screening window to wear the actigraph for at least 7 consecutive 
collected for 7 consecutive days before travel for the baseline visit. Subjects will be given 3
actigraph will remain in the study.
Subjects who are assigned study drug but are subsequently not compliant with wearing the
actigraph for 7 consecutive days prior to the baseline visit) will be excluded from the study.
with the actigraph guidelines during the screening period (subjects must be able to wear the
to tolerate wearing the device. Subjects who are not able to tolerate the actigraph and/or comply 
sensitivities exist in the study population, and it is anticipated that some subjects will not be able
effort should be made to keep the location the same throughout the study. Severe sensory
acceptable for the subject. Once a body location is selected for attachment of the actigraph, every
the ankle or hip. The actigraph can be attached with a hospital band if that makes it more
time, and the data must be uploaded to an actigraphy database for analysis.
actigraph measures sleep and daytime activity. The actigraph unit stores motion data by clock
Sleep Diary
Actigraphy
scheduled study site visits at Week 6 and Week 12 visits to collect at least 7 consecutive days of


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On Day 1, all subjects will take their first dose of study drug at the study site during the daytime,
At each clinic visit when a sleep diary is issued (Table 6–1), a calendar will be issued to remind
the LAR/caregiver when next to start recording data in the sleep diary. In addition, study site  
staff will remind the LAR/caregiver by phone call when it is time to start recording data in the  
sleep diary. Sleep diaries will be collected at visits per Table 6–1.  
6.3 
 
 
 
 
 
 
 
 
 
At the EOS, OV101 concentration and time data obtained from sparse sampling in this study will
subsequently be subjected to population PK modeling and resulting exposure estimates will be  
evaluated using validated physiologically-based PK (PBPK) modeling to confirm predicted  
exposure estimates for the pediatric study population 2 to 12 years old at various weight bands.  
Pharmacokinetic endpoints are presented in Section 7.2.3.  
6.4 Safety Assessments 
Safety assessments will include frequency, severity, and causality of AEs (including SAEs and 
AEs leading to study discontinuation), and other safety assessments including assessment of 
suicidality, collection of seizure diaries, clinical laboratory assessments, vital sign measurements, 
and physical examinations. Safety assessments will be conducted according to the schedule 
presented in Table 6–1 for all age groups (2 to 12 years of age). 
that individual OV101 concentration-time data align with respective data obtained previously
from adolescents. Further details will be provided in the IDMC charter. 
age). Plasma concentrations within each time window will be evaluated by the IDMC to confirm
3 evaluable sentry subjects receiving OV101 within each age band (9 to 12 and 4 to 8 years of
each of the above 3 time points following the initial dose will be determined from a minimum of 
is permitted if necessary. Approximately 2 mL of blood will be collected per PK sample for a 
total of 6 mL during Day 1. Blood samples will be processed to plasma within 2 hours. Plasma 
samples will be frozen, stored and shipped according to instructions to be provided to the study 
site. The PK samples will be analyzed for OV101 concentrations by a Sponsor-contracted 
bioanalytical facility using a validated bioanalytical assay. Plasma concentrations of OV101 for
dosing and the time of blood sampling. Topical application of a cooling agent or local anesthetic 
and blood will be sampled for determination of plasma OV101 concentrations at 3 time points 
following the initial dose: 45 minutes ± 15 minutes; 90 minutes ± 15 minutes, and 4 hours ± 30 
minutes (sparse sampling for population PK modeling). Study site staff will record the time of 
Pharmacokinetic Assessments
from adolescents. Further details will be provided in the IDMC charter.
that individual OV101 concentration-time data align with respective data obtained previously
3 evaluable sentry subjects receiving OV101 within each age band (9 to 12 and 4 to 8 years of
bioanalytical facility using a validated bioanalytical assay. Plasma concentrations of OV101 for
site. The PK samples will be analyzed for OV101 concentrations by a Sponsor-contracted
samples will be frozen, stored and shipped according to instructions to be provided to the study
total of 6 mL during Day 1. Blood samples will be processed to plasma within 2 hours. Plasma
is permitted if necessary. Approximately 2 mL of blood will be collected per PK sample for a
minutes (sparse sampling for population PK modeling). Study site staff will record the time of 
following the initial dose: 45 minutes ± 15 minutes; 90 minutes ± 15 minutes, and 4 hours ± 30
and blood will be sampled for determination of plasma OV101 concentrations at 3 time points


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or is unable to tolerate wearing the actigraph.
6.4.1 Adverse Events 
6.4.1.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or severity. Each subject’s LAR/caregiver 
will be instructed to contact the study center if the subject experiences any adverse events (AEs), 
is unable to take the study drug as prescribed, 
 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study drug. Subjects will be instructed to contact the 
investigator at any time after enrollment if any symptoms develop. 
 
Treatment-emergent AEs (TEAEs) are defined as AEs that start or increase in severity after the 
first dose of study drug in the study. 
 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) and anticipated day-to-day fluctuations of preexisting disease(s) or 
condition(s) present or detected at the start of the study that do not worsen are not AEs. Lack of 
drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect. 
 
Cases of pregnancy that occur during maternal or paternal exposures to study drug are to be 
reported. Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug 
safety evaluation. 
 
Study site personnel will record the occurrence and nature of each subject’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study (e.g., seizures, motor dysfunction, sleep disruption, anxiety), as part of the medical 
history. 
 
As seizures are often a baseline condition in subjects with AS, seizures should be reported as an 
AE in any of the following circumstances: 
 
x There is a clear increase in the frequency of seizures compared to the subject’s baseline. 
 
x There is an emergence of a new seizure type. 
 
x The subject experiences status epilepticus. 


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 The investigator believes the seizure should be captured as an AE (in which case the 
investigator should document his/her reasoning). 
 
Seizures in this subject population will be detected and assessed using the seizure diary 
(Section 6.4.2.2). Diaries will be collected at the study site during the study and will be analyzed by 
the Sponsor along with the reportable SAEs in evaluating risks and benefits. The Sponsor will report 
the SAE events of seizure that meet these criteria in an aggregated, unblinded report at the end of the 
study. 
 
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs. If a subject experiences an AE after the 
ICF has been signed but before receiving study drug, the event will be reported and will be 
included in the subject’s medical history unless the event is serious or the investigator feels the 
event may have been caused by a protocol procedure. 
 
In addition, all AEs occurring after the subject receives the first dose of study drug must be 
reported to Ovid or its designee via the eCRF. 
 
6.4.1.2 
Serious Adverse Events 
An SAE is defined as any event that 
 
 Results in death. 
 Is immediately life threatening. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly or birth defect. 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


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6.4.1.3 
Eliciting and Documenting Adverse Events 
Adverse events will be assessed beginning on the date of signed informed consent and up to 
14 days after the last dose of study drug (unless a subject decides to participate in the ELARA 
open-label extension study) and must be followed until resolution or for 14 days after the 
subject’s last study drug dose, whichever comes first. 
 
Serious AEs that occur more than 30 days after the last dose of study drug need not be reported 
unless the investigator considers them related to study drug. 
 
After informed consent is obtained, at every clinic visit and phone visit, subjects and their 
LAR/caregiver will be asked a standard nonleading question to elicit any medically-related 
changes in their well-being. They will also be asked if they have been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and over-the-counter medications). 
 
In addition to subject observations, AEs identified from any study data (e.g., laboratory values, 
physical examination findings) or identified from the review of other documents (e.g., subject 
diaries) that are relevant to subject safety or considered to be clinically significant, in the medical 
and scientific judgment of the investigator, will be documented on the AE page in the eCRF. 
 
6.4.1.4 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 
 
 Drug treatment 
 
 Dose 
 
 Event term 
 
 Time of onset 
 
 Investigator-specified assessment of severity and relationship to study drug 
 
 Time of resolution of the event 
 
 Seriousness 
 
 Any required treatment or evaluations 


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 Outcome 
 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs will be 
followed to adequate resolution. The Medical Dictionary for Regulatory Activities (MedDRA) 
will be used to code all AEs. 
 
Any medical condition that is present at the time the subject is screened and remains stable 
should not be reported as an AE. However, if the condition worsens at any time during the study, 
it should be recorded as an AE. 
 
Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (e.g., vital sign measurements), including those that worsen from baseline, that are 
felt to be clinically significant in the medical and scientific judgment of the investigator are to be 
recorded as AEs. 
 
6.4.1.5 
Reporting Serious Adverse Events 
All nonserious AEs must be recorded in the eCRF upon awareness. 
 
Any AE that meets SAE criteria (Section 6.4.1.2) must immediately (i.e., within 1 business day) 
inform Ovid Drug Safety upon learning of any SAE that occurs (whether or not attributable to 
the study drug). It is the investigator’s responsibility to ensure that SAE reporting procedures are 
followed appropriately. All SAE reports and any revisions to an SAE report must be sent to the 
email provided. All supporting source information concerning the SAE (e.g., hospital records) 
should also be provided by fax or email. 
 
Country-specific fax numbers will be provided in a separate document. 
Email: ovidCTsafety@ovidrx.com 
 
If there is a question concerning an SAE, the site needs guidance regarding the reporting of an 
SAE, the site is returning a call from an Ovid Drug Safety specialist, the site urgently needs to 
report an SAE or make Ovid Drug Safety aware of an SAE, the safety hotline should be used 
(country-specific hotline numbers provided in a separate document). 
 
If an SAE is reported via the hotline, the site should first submit the SAE paper form and then 
enter the SAE in the eCRF. Any AE that meets SAE criteria (Section 6.4.1.2) must be entered 
into the EDC system immediately (i.e., within 1 business day) after site personnel first learn 
about the event, in addition to faxing/emailing the SAE Report form. Once the qualifying SAE 


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data are entered into the EDC system, Ovid will be notified by an email alert, which will contain 
high-level safety information. 
 
All SAEs must be reported starting from the time that informed consent for study participation is 
provided. If the investigator becomes aware of an SAE within 30 days after the subject’s last 
dose of study drug or within 30 days after the last study visit, the SAE must be reported unless 
the patient has signed the consent to enroll into the ELARA open label extension study. Serious 
AEs must be followed until the event resolves, the event or sequelae stabilize, or it is unlikely 
that additional information can be obtained after demonstration of due diligence with follow-up 
efforts (i.e., the subject or health care practitioner is unable to provide additional information, or 
the subject is lost to follow-up). For subjects who do not sign the informed consent to enroll into 
the ELARA open label extension study, serious AEs that occur more than 30 days after the last 
dose of study drug should be submitted to the sponsor if the investigator becomes aware, 
however, these do not need to be reported to the IRB/EC or regulators unless the investigator or 
Sponsor considers them related to study drug. 
 
6.4.1.6 
Suspected Unexpected Serious Adverse Reactions and Nonserious 
Adverse Events of Special Interest 
The Sponsor will promptly evaluate all suspected unexpected serious adverse reactions and 
nonserious AEs of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs and IECs, and 
applicable health authorities based on applicable legislation. 
 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the current OV101 investigator’s brochure (Ovid 
Therapeutics Inc. 2018). 
 
The Sponsor or its legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria. This protocol will use Appendix 1 of the 
current investigator’s brochure as the Reference Safety Document. The expectedness and 
reporting criteria of an SAE will be determined by the Sponsor from the Reference Safety 
Document. 
 
6.4.1.7 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s daily 
activities. The intensity of the AE will be rated as mild, moderate, or severe using the following 
criteria: 


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Mild:
An AE that is transient in nature and generally does not interfere with the 
subject’s normal activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with the subject’s normal 
activities. 
Severe: 
An AE that is incapacitating and prevents normal activities. 
 
 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of onset and duration of each episode. 
 
6.4.1.8 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. 
 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
 
Unrelated:
This relationship suggests that there is no association between the study drug 
and the reported event. 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, i.e., the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to the 
study drug but could also have been produced by other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the study drug seems likely. The event 
disappears or decreases on cessation or reduction of the dose of study drug. 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the study 
drug is re-administered. 


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6.4.1.9 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered stable. 
 
6.4.2 Other Safety Assessments 
Safety assessments other than AEs (Section 6.4.1) include assessment of suicidality, collection of 
seizure diaries, clinical laboratory analyses (Section 6.7), vital sign measurements, and physical 
examinations. 
 
6.4.2.1 
Assessment of Suicidality 
The ABC-I will be used to assess suicidality instead of the Columbia-Suicide Severity Rating 
Scale, since cognitive impairment in Angelman syndrome patients interferes with the 
understanding of the concept of suicide. Most individuals with AS are not able to communicate 
thoughts of suicidality, so the subject’s irritability reported by the LAR/caregiver is being used as 
a surrogate measure of suicidality. The investigator will review the scale items with the 
LAR/caregiver at each scheduled time point. If grading worsens, the investigator must decide 
whether that indicates a potential for self-harm by the subject, and if so, must document it as an 
AE and closely monitor it until resolution. The entire Aberrant Behavior Checklist – Community 
(ABC-C) will be administered although only the ABC-I will be used to assess the potential for 
self-harm. 
 
6.4.2.2 
Seizure Diary 
The seizure diary is a caregiver-reported clinical outcome assessment measure that captures the 
total number and duration of seizures. Caregivers will record the number, duration, and type of 
seizures each day using the paper seizure diary. Also, refer to Section 6.4.1.1 for AE reporting 
criteria for these seizure events. 
 
The caregiver will be trained by the site with specific instructions beginning with the screening 
visit to ensure compliance in recording seizures. The seizure diary will be completed each day 
during 12 weeks of treatment beginning at screening and continuing through the EOT. Seizure 
diaries will be collected and reviewed by the investigator with the subject’s caregiver for proper 
recording at the baseline, Week 6, and Week 12 (or EOT) study site visits. Seizure Identification 
Form and Diagnostic Review Forms (SIF/DRF) will be completed by site personnel for every 
eligible subject. This information will be faxed or emailed to The Epilepsy Study Consortium 
(TESC) for review and approval. The SIF/DRF will be used to ensure that the seizures are 


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classified accurately. SIF and DRF forms will be collected for patients who have 
enrolled/completed the study if feasible. 
 
For the prospective baseline period, the seizure frequency (expressed as a 28-day frequency) will 
be calculated as 
 
(# of seizures) / (# of days seizures were assessed)  28 
 
Seizure frequency calculated through this method will be used to confirm the eligibility. 
 
6.4.2.3 
Vital Sign Measurements 
Vital sign measurements will include blood pressure, temperature, heart rate, and respiratory rate. 
Measurement of vital signs should be attempted after the subject has been resting in a supine or 
sitting position for at least 10 minutes. 
 
6.4.2.4 
Physical Examinations 
Height, weight, and head circumference will be measured as part of the physical examination, 
but height will be measured only at the screening visit. A physical examination will include a 
relevant general assessment of: general appearance; skin; head, eyes, ears, nose and throat; neck; 
lymph nodes; chest (including lungs); heart; abdomen; extremities; nervous system; and 
musculoskeletal system. 
 
6.4.2.5 
Exposure During Pregnancy and/or Lactation 
OV101 should not be administered to pregnant or lactating females because the potential for 
adverse reactions to OV101 in pregnant females, fetuses, and nursing infants is unknown. 
 
Pregnancy data will be collected during this study for all subjects. Exposure during pregnancy 
(also referred to as exposure in-utero) can be the result of either maternal exposure or 
transmission of drug product via semen following paternal exposure. 
 
For all Ovid products, both in development or post-approval, exposure during pregnancy must be 
recorded and the subject followed until the outcome of the pregnancy is known (spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality), even if the subject 
discontinues study drug or discontinues from the study. 
 
If a subject within this study or a subject’s partner becomes pregnant while treated or exposed to 
study drug, the investigator must submit a pregnancy form to Ovid via the same method as SAE 
reporting. Pharmacovigilance will supply the investigator with a copy of a “Pregnancy Reporting 


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and Outcome Form/Breastfeeding.” When the outcome of the pregnancy becomes known, the 
form should be completed and returned to Ovid or Ovid Pharmacovigilance delegate. If 
additional follow-up is required, the investigator will be requested to provide the information. 
 
Exposure of an infant to an Ovid product during breastfeeding must also be reported and any 
AEs experienced by the infant must be reported to Ovid Pharmacovigilance or designee via 
email or fax (Section 6.4.1.5). 
 
Pregnancy is not regarded as an AE unless there is a suspicion that study drug may have 
interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet criteria for an SAE (such 
as ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs 
 
6.5 Safety Monitoring Committee 
An IDMC (Section 11.1.1) will provide safety monitoring. Oversight of the study conduct and 
IDMC will be provided by the Clinical Trial Steering Committee (CTSC; Section 11.1.2). 
 
Routine pharmacovigilance oversight will be provided by Ovid Drug Safety. 
 
6.6 Pregnancy 
Female subjects who are of childbearing potential (defined as having experienced their first 
menarche) must agree to use either a highly effective or acceptable form of birth control during 
the study and for 30 days following the last dose of the study. Highly effective contraceptive 
methods are as follows: 
 
a. Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
 
 Oral 
 Intravaginal 
 Transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 
 Oral 
 Injectable 
 Implantable 
c. Intrauterine device 


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d. Intrauterine hormone-releasing system 
 
e. Bilateral tubal occlusion 
 
f. Vasectomized partner 
 
g. Sexual abstinence 
 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
 
a. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action. 
 
b. Male or female condom with or without spermicide. 
 
c. Cap, diaphragm or sponge with spermicide. 
 
d. A combination of male condom with either cap, diaphragm, or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods 
 
For male subjects with women of child-bearing potential partners, there are no restrictions. 
Female subjects who have experienced menarche will undergo serum beta-human chorionic 
gonadotrophin (ß-hCG) pregnancy testing at study site visits shown in Table 6–1 (as part of the 
sampling for clinical laboratory tests). Any female subject with a positive pregnancy test result at 
Screening must be excluded from the study. A serum ß-hCG pregnancy test must be performed if 
any female subject is suspected of becoming pregnant during the study. 
 
If pregnancy occurs at any time during the study, study drug must be discontinued immediately 
(or not started). Pregnancy is not regarded as an AE unless there is a suspicion that a study drug 
may have interfered with the effectiveness of a contraceptive medication. Any pregnancy that 
occurs during study participation must be reported using the same procedures as an SAE 
(Section 6.4.1.5) but using a clinical study pregnancy form. The pregnancy must be followed-up 
to determine outcome (including spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) and status of mother and child, even if the subject is discontinued from 
the study. Pregnancy complications and elective terminations for medical reasons should not be 
reported as an AE or SAE. Spontaneous miscarriages must be reported as an SAE. 


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Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to the 
study treatment, must be promptly reported to Ovid Drug Safety. 
 
6.7 Laboratory Analyses 
The following clinical analytes will be assayed as safety assessments: 
 
Hematology: hematocrit; hemoglobin; red blood cell count with indices (mean corpuscular 
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration); 
reticulocytes; white blood cell count and differential (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) reported as percentages and absolute values; and platelets (platelet 
count, prothrombin time and partial thromboplastin time, international normalization ratio). 
Clinical chemistry: albumin; alkaline phosphatase; blood urea nitrogen; gamma-glutamyl 
transferase; calcium; creatinine; glucose; cholesterol (high-density lipoprotein and low-density 
lipoprotein [calculated] and homogenous low-density lipoprotein); triglycerides; magnesium, 
phosphate; potassium; alanine aminotransferase; aspartate aminotransferase; lactate 
dehydrogenase; sodium; chloride; bilirubin (total, direct); total protein; uric acid; and creatine 
phosphokinase. 
Pregnancy testing: Serum ß-hCG for female subjects who have experienced menarche. Serum 
pregnancy testing will be conducted at screening and baseline. Serum pregnancy testing is 
recommended at subsequent visits; however, urine pregnancy testing is allowed if serum is not 
obtainable. If serum cannot be collected, the reason should be documented in the source 
document and, for sexually active female subjects, the results of the serum pregnancy test 
obtained at Visit 1 must be confirmed to be negative by the investigator before randomization. 
 
6.8 Sample Collections 
Blood samples collected from subjects will be forwarded to a central laboratory for analysis. 
Further details regarding sample collections and processing and specific testing can be found in 
the study manual (provided to study sites as a separate document). 
 
All samples for clinical laboratory analysis will be collected as described in the study manual, 
according to the schedule of activities (Table 6–1). Samples for hematology and clinical 
chemistry will be used only for the evaluation of safety and tolerability. 
 
Blood samples will be collected for clinical laboratory, safety assessments, 
A total of up to 7 mL of blood is expected to be taken for laboratory measurements at 
assays.
and for sparse PK


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plasma will be frozen until analyzed.
Blood samples for PK assays will be processed to plasma within 2 hours of being drawn, and
each of the screening, baseline, Week 6, and Week 12 visits. Total blood collected will not 
exceed 20 mL in a 30-day period. This is in accordance with the US Department of Health and 
Human Services, office for Human Research Protections recommendations of 3 ml/kg, up to 50 
ml total within 8 weeks (Table 2 in Howie 2011). 
6.9 
Contraception and Pregnancy Avoidance Procedure 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy, donation of ova, and sperm donation 
during the course of the study and for 90 days after the last dose of study drug. This may be 
signed by the LAR/caregiver of the subject. For additional details, refer to Section 6.6 for 
detailed contraception requirements. 
Female subjects who have experienced menarche must have a negative serum/urine hCG 
pregnancy test at screening (Visit 1) and a negative serum hCG pregnancy test on Day 1 (Visit 
2), before receiving any dose of study drug. If pregnancy results cannot be collected at Visit 2, 
the reason should be documented in the source document, the results of the serum pregnancy test 
obtained at Visit 1 must be confirmed to be negative by the Investigator prior to randomization, 
and results of a serum pregnancy test at Visit 2 must be confirmed to be negative before the 
subject can receive the first dose of study drug. During the study, subjects will receive continued 
guidance with respect to the avoidance of pregnancy and ova or sperm donation as part of the 
study procedures. An additional serum/urine hCG pregnancy test will be performed at the final 
visit. 


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7 
Statistical and Analytical Plan 
7.1 General Considerations 
All statistical analyses will be performed using SAS® Version 9.4 or higher. All clinical study 
data will be presented in subject data listings. Data summaries will be presented for all endpoints 
and will include descriptive statistics (number of subjects, mean, SD, first quartile, median, third 
quartile, minimum, and maximum) for continuous variables, and frequency and percentage for 
categorical and ordinal variables. If there are missing values, the number of missing values will 
be presented, but without a percentage. 
 
For all analyses, “baseline” refers to the most recent non-missing value obtained immediately 
prior to administration of first dose, unless it is otherwise clearly defined. 
 
Any substantial change to the data analysis methods described in the protocol will require an 
amendment. Any other change to the data analysis methods described in the protocol, and the 
justification for making the change, will be described in the SAP. Additional post hoc analyses of 
the data may be conducted as deemed appropriate. 
 
7.2 Endpoints 
7.2.1 Efficacy Endpoints 
7.2.1.1 
Primary Endpoint 
x The CGI-I-AS score at Week 12 
 
7.2.1.2 
Key Secondary Endpoints 
The key secondary endpoints will be utilized to fulfil a recommendation of the EMA for a 
responder analysis.  
x CGI-I-AS response (at least minimally improved) defined as CGI-I-AS score of 1, 2, or 3 
at Week 12 
x CGI-I-AS response (at least much improved) defined as CGI-I-AS score of 1 or 2 at 
Week 12 
7.2.1.3 
Other Secondary Endpoints 
x
x
sleep onset
Latency of sleep onset (LSO), defined as time from beginning of rest period to start of
Actigraphy assessment scores, change from baseline to Week 12


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Total sleep time at night defined from subject time of sleep onset to time of
Sleep efficiency defined as the percentage of total sleep time out of the duration
x
Total daytime sleep, defined as duration of sleep time in the active interval
7.2.1.4
Tertiary Endpoints
x
Sleep diary assessment scores, change from baseline to Week 12
o
o
Latency of sleep onset defined from subject in bed to time of subject sleep onset
o
x
CSHQ assessment scores, change from baseline to Week 12
x
x VABS-3 assessment scores; change from baseline to Week 12 
o Communication domain and its subdomains 
o Socialization domain and its subdomains 
o Daily Living Skills domain and its subdomains 
o Motor Skills domain and its subdomains 
o Maladaptive Behavior domain and its subdomains 
x The CGI-S-AS scores, change from baseline to Week 12. 
o The CGI-S-AS symptoms overall score 
o The CGI-S-AS domain scores 
x The relationship between CGI-S-AS at baseline and CGI-I-AS at Week 12 
x The relationship between each of CGI-S-AS domains at baseline and CGI-I-AS at 
Week 12 
x










awakening
of time in bed
period
Sleep efficiency, defined as the percentage of total sleep time out of duration of the rest
Daytime sleep defined as duration of napping
Number of disruptive behaviors while in bed 
Duration of night awakenings
Number of night awakenings 
HQ
o 
o 
o
o
Daily activity level (counts/minute) in the daily interval
Total sleep time at night defined as duration of sleep time in the sleep interval
eep
o
o
Actigraphy assessment scores, change from baseline to Week 12
x
x
Total sleep time at night defined from subject time of sleep onset to time of
Total sleep 
awakening
Total sleep
Total sleep
Sleep efficiency defined as the percentage of total sleep time out of the duration
Sleep efficienc
of
Sle
Sl time
eep e
eep e in
ffic
ffi bed
cienc
ien
x


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x
minutes ± 15 min, 4 hours ± 30 min).
OV101 plasma concentration at each PK sampling window (45 minutes ± 15 min, 90
x
model.
estimates (Cmax and AUC) will also be evaluated in the context of a validated PBPK
OV101 PK parameters derived from population PK modelling: Population PK exposure
 







 
7.2.2 Safety Endpoints 
x Incidence of AEs 
x Change in clinical laboratory parameters from baseline to each post baseline assessment 
x Shift in clinical laboratory parameters from baseline to each post baseline assessment 
x Change in vital sign measurements from baseline to each post baseline assessment 
x Shift in physical examination parameters from baseline to each post baseline assessment 
x Change in suicidality assessment (ABC-I) from baseline to each postbaseline as assessed 
by ABC-I. The ABC-I will serve as a surrogate measure for suicidality 
x Percent change in seizure frequency (expressed as a 28-day frequency) from baseline to 
each post baseline timepoint 
 
7.2.3 
 
 
12
Pediatric Quality of Life Inventory™ assessment scores, change from baseline to Week
x
Sleep-Onset Delay Subscale score
Family Impact module scores by dimension, total scores including the Parent 
HRQL Summary Score, the Family Functioning Summary Score 
Multidimensional Fatigue module by dimension and total score
Cerebral Palsy module by dimension score
o
o 
o
Morning Waking/Daytime Sleepiness Subscale score
Sleep-Disordered Breathing Subscale score
Parasomnias Subscale score
Behavior Occurring Around Night Wakings Subscale score
Anxiety Around Sleep Subscale score
Sleep Duration Subscale score
Bedtime Resistance Subscale score
Total score
o 
o 
o 
o 
o 
o 
o 
o
o
Pharmacokinetic Endpoints
x
x
Sleep-Onset Delay Subscale score
x


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Sample size calculations were performed to determine the number of subjects needed for
The sample size calculations are based on comparison of the CGI-I-AS score at Week 12
As a sensitivity analysis of the assumption of normality, a Wilcoxon rank sum test will be
 
 
Approximately 95 subjects will be included in the study at approximately 15 study sites with no
more than 12 subjects 4 to 12 years old per study site (unless authorized by the  
Sponsor).Approximately 90 subjects 4 to 12 years old (inclusive) will be randomly assigned in a
1:1 ratio into OV101 or placebo treatment groups for both efficacy and safety assessments.  
Randomization will be stratified by age categories: 9 to 12 years old (inclusive) and 4 to 8 years
old (inclusive) and region (US and Outside US). It is intended that a minimum of 24 subjects are
randomized for each age category. Approximately 5 subjects 2 to 3 years old (inclusive) will be 
included and treated with OV101 for safety assessments only.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the primary analysis of CGI-I-AS shows a significant difference between OV101 QD and  
placebo, two key secondary endpoints, CGI-I-AS response (at least minimally improved) at
Week 12 and CGI-I-AS response (at least much improved) at Week 12 will be used to test the
difference between OV101 and placebo with a gated sequential testing procedure at a 2-sided
the placebo group, and 0, 0.296, 0.37, 0.334, 0, 0, 0 in the OV101 QD group.
0.074, 0, 0 for the probability of each CGI-I Symptoms Overall at Week 12 response category in
with probability distributions observed in OV101-15-001 Phase 2 study: 0, 0.074, 0.148, 0.704, 
significance. This calculation is based on the assumption of 7 ordered categories (scaled 1-7)
difference of OV101 versus placebo using a Wilcoxon rank-sum test at a 2-sided 0.05 level of
conducted. With 40 subjects per treatment group, there would be 99% power to test the treatment
difference at a 2-sided 0.05 level of significance.
variances, with 40 subjects per treatment group, there would be 99% power to test the treatment
of the CGI-I-AS at Week 12 between OV101 and placebo, using a two-sample t-test with equal
common standard deviation of 0.8 points, which yields an effect size of 1. Based on comparison
points between OV101 QD and placebo in the CGI-I Symptoms Overall score at Week 12 with a
derived from the results observed in the OV101-15-001 Phase 2 study: a mean difference of 0.8
between OV101 and placebo, using a two-sample t-test with equal variances. Assumptions are
secondary endpoints.
are required to ensure sufficient power for significance testing using the primary and both key
endpoints. Based on these calculations, a minimum of 40 evaluable subjects per treatment group
evaluation of efficacy using the primary efficacy endpoint as well as the two key secondary
7.3 Sample Size and Power
of the CGI-I-AS at Week 12 between OV101 and placebo, using a two-sample t-test with equal


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With 40 subjects per treatment group, there would be 99% power to test the treatment difference
Table 7–1 summarizes the power calculations for all three endpoints:
Table 7–1
Power Calculations
 
 
 
 
 
 
 
 
 
 
 
 
Endpoint  
Primary Endpoint
CGI-I-AS At Least
CGI-I-AS At Least
 
 
 
CGI-I-AS  
 
Minimally  
 Much Improved  
 
Improved
 
Test Significance  
 
0.05  
 
0.05  
 
0.05
Level, α  
 
 
 
1 or 2 Sided Test  
 
Two  
 
Two  
 
Two
Assumptions  
 
μ₁ - μ₂=0.8 and  
 
π₁=0.21, π2=0.67  
 
π₁=0.07, π2=0.32  
 
 
σ=0.8 
 
 
Power (%)  
 
99%  
 
99%  
 
81.8%  
Sample Size per  
40 
40 
40 
Group, n 
n, assuming 10%  
45 
45 
45 
Dropout  
Assuming a 10% drop-out rate, 90 subjects aged 4 to 12 years old will be randomized to OV101
QD and placebo (1:1 randomization).  
7.4 Analysis Sets 
The following analysis sets will only include subjects 4 to 12 years old (inclusive). The analysis 
for subjects 2 to 3 years old (inclusive) will be conducted separately. 
The intent-to-treat set will consist of all subjects who are randomized, whether or not study drug 
is received. Subjects will be analyzed according to their randomized group 
OV101 QD.
response (at least much improved), assuming a response rate of 7% for placebo and 32% for
difference of OV101 versus placebo based on the second key secondary endpoint, CGI-I-AS
With 40 subjects per treatment group, there would be 81.8% power to test th
minimally improved), assuming a response rate of 21% for placebo and 67% for OV101 QD.
of OV101 versus placebo based on the first key secondary endpoint, CGI-I-AS response (at least
15-001 Phase 2 study.
proportions. Assumptions regarding response rates are based on the rates observed in OV101-
0.05 level of significance. Power calculations were performed based on chi-square test of two
45
45
45 
40
40
40 


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and
least 1 valid PK measurement.
The PK data set will consist of all subjects who receive at least 1 dose of study drug and have at
The full analysis set (FAS) will include all subjects who are randomized, receive at least 1 dose 
of study drug, and have at least 1 post baseline assessment of the primary efficacy endpoint. The 
FAS will be used for efficacy analyses based on the randomized treatment for each subject. 
The per protocol set (PPS) is a subset of the FAS that includes subjects who complete the Week 
12 visit and have no major protocol deviations that are deemed to impact efficacy. The PPS will 
be used for efficacy analyses based on the randomized treatment for each subject.  
The safety set (SS) will consist of all subjects who are randomized and receive at least 1 dose of 
study drug and will be used for all safety analyses. The safety analyses will be based on the 
treatment that was actually administered to each subject. 
7.5 Subject Disposition 
The number of subjects screened and who failed screening will be displayed. The number and 
percentage of subjects who are randomized, dosed, withdrawn from the study (including reasons 
for withdrawal), and complete the study will be displayed by treatment group and overall for the 
intent-to-treat set. The number and percentage of randomized subjects in the SS, FAS, PPS, 
PK data set will also be displayed by treatment group and overall. 
The number of subjects screened, dosed, completed study, and withdrawn from the study will be 
summarized separately for subjects 2 to 3 years old (inclusive). 
7.6 Demographic and Baseline Characteristics 
Demographic characteristics include age at screening and at baseline, age group (randomization 
stratification variable: age at screening 4 to 8 years versus age 9 to 12 years), region 
(randomization stratification variable: US versus outside US), gender, race, ethnicity, study 
center, and country. Baseline characteristics include baseline body weight, height, body mass 
index (kg/m2), and molecular diagnosis. All demographic and baseline characteristics data will 
be summarized descriptively by treatment group and overall for the SS. 
 
Data for subjects 2 to 3 years old (inclusive) will be presented separately in listings. 
 
7.7 Exposure and Compliance 
Treatment compliance will be summarized by treatment group over the entire treatment period. 
Compliance rates during the treatment period will be derived using the following formula: 
PK 


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100× (Total number of capsules dispensed–Total number of capsules returned) / (Expected 
number of capsules) 
 
The expected number of capsules to be taken is based on the date of first study drug dose and the 
date of last study drug dose, the subject’s weight range band at screening that determines the 
number of capsules expected each study week, following the titration schedule (Section 5.1), and 
any dose down-titrations (Section 5.2.1). Compliance rates will be presented for the SS using 
summary statistics and percentage for the frequency distributions (0% to <20%, 20% to 40%, 
40% to <60%, 60% to <80%, 80% to <100%, 100% to ≤120%) by treatment group and overall. 
 
Data for subjects 2 to 3 years old (inclusive) will be presented separately in listings. 
 
7.8 Efficacy Analyses 
All efficacy analyses will be based on the FAS. Additionally, the analysis of the primary endpoint 
will be repeated on the PPS to assess the sensitivity of the results to major protocol violations. 
All efficacy variables will be summarized descriptively by treatment group and visit. 
 
7.8.1 Primary Efficacy Analyses 
The CGI-I-AS scale assessed by the clinician rater will be collected at the Week 6 and Week 12 
visits. This is an ordinal variable with scores ranging from 1 (very much improved), to 4 (no 
change), to 7 (very much worse) which will be analyzed as a continuous outcome variable in 
these analyses. 
 
An MMRM Analysis of Variance (ANOVA) model will be fitted using restricted maximum 
likelihood (REML) for CGI-I-AS with fixed effects for visit (Week 6 and Week 12), randomized 
treatment, the visit-by-treatment interaction, age group (randomization stratification variable: age 
4 to 8 years versus age 9 to 12 years), and region (randomization stratification variable: US 
versus outside US). An unstructured within -subject covariance structure will be specified as the 
first choice, and if the model fails to converge, alternative covariance structures will be tested as 
detailed in the SAP. If a structured covariance is used, then a robust sandwich estimator will be 
utilized for estimating the variance of the treatment effect estimate. From the model, the Week 12 
difference between least squared means of OV101 and placebo groups will be presented along 
with the corresponding 95% confidence interval and 2-sided P value. 
 
As a sensitivity analysis for the assumption of normality, a Wilcoxon rank sum test will be used 
for treatment group comparison. The Hodges–Lehmann (Hodges and Lehmann 1963) estimate of 


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For each subject, the average of daily values for each actigraphy variable (LSO, sleep efficiency,
An MMRM Analysis of Covariance (ANCOVA) model for the change from baseline (7day
the median CGI-I-AS difference between OV101 and placebo groups, and its 95% confidence 
interval will be presented along with the 2-sided P value. 
 
7.8.2 Key Secondary Efficacy Analyses 
Generalized Estimating Equations (GEE) method will be used for the analysis of key secondary 
endpoints: CGI-I-AS response (at least minimally improved) and CGI-I-AS response (at least 
much improved). GEE models will include the response variable at each visit as the dependent 
variable, and fixed effects for visit (Week 6 and Week 12), randomized treatment, the visit-by- 
treatment interaction, age group (randomization stratification variable: age 4 to 8 years versus 
age 9 to 12 years), and region (randomization stratification variable: US versus outside US). An 
unstructured working correlation for the binary outcome variable will be assumed for the model 
parameter estimation, and if the model fails to converge, alternative covariance structures will be 
tested as detailed in the SAP. If there is no response in either treatment arm at the Week 6 visit, 
the GEE model will be substituted with a logistic regression for the Week 12 CGI-I-AS response 
variable with effects for the randomized treatment and the two randomization stratification 
variables. From the model (GEE or logistic regression, as appropriate), the Week 12 odds ratio 
will be presented along with the corresponding 95% confidence interval and 2-sided P value. 
7.8.3 Other Secondary Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
The VABS-3 composite scores (Communications, Socialization, Daily Living Skills, Motor 
Skills, and Maladaptive Behavior domains) and scores of their subdomains will be assessed at 
baseline and Week 12 and analyzed as continuous outcome variables. 
interval and 2-sided P value.
OV101 and placebo groups will be presented along with the corresponding 95% confidence
detailed in the SAP. From the model, the Week 12 difference between least squared means of
choice, and if this analysis fails to converge, alternative covariance structures will be tested as
a covariate. An unstructured within-subject covariance structure will be specified as the first
(randomization stratification variable: US versus outside US), and the corresponding baseline as
(randomization stratification variable: age 4 to 8 years versus age 9 to 12 years), region
(Weeks 6 and 12), randomized treatment, the visit-by-treatment interaction, age group
average) will be fitted for each actigraphy endpoint defined above with fixed effects for visit
Week 12).
and total daytime sleep) will be calculated for 7 days prior to each visit (baseline, Week 6, and
An MMRM Analysis of Covariance (ANCOVA) model for the change from baseline (7day


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7.8.4 Tertiary Analyses
The CSHQ total score and scores of its subscales will be treated as a continuous outcome
The Peds QL module scores will be treated as continuous outcome variables. For each module
Change from baseline to Week 12 in each VABS-3 domain score and scores of their subdomains 
will be analyzed using an ANCOVA model with effects for randomized treatment, age group 
(randomization stratification variable: age 4 to 8 years versus age 9 to 12 years), region 
(randomization stratification variable: US versus outside US), and the corresponding baseline as 
a covariate. A test for a significant treatment-by-baseline interaction will be performed in a 
separate model (including the above terms plus the interaction term), using a 0.100 alpha level. If 
the treatment-by-baseline interaction is significant, then the ANCOVA assumptions are violated 
and an ANOVA model will be used instead. From the final model(s), the difference between least 
squared means of OV101 and placebo groups will be presented along with the corresponding 
95% confidence intervals and 2-sided P values. 
 
The CGI-S-AS Symptoms Overall and CGI-S-AS domains will be collected at baseline, Weeks 
6, and 12, and will be treated as a continuous outcome variable. An MMRM ANCOVA 
methodology similar to the one described previously for actigraphy variables will be used to 
analyze the change from baseline in CGI-S-AS Symptoms Overall score and in scores of CGI-S- 
AS domains. 
 
The relationships between CGI-S-AS Symptoms Overall score at baseline and CGI-I-AS at 
Week 12 will be explored. The relationships between each of CGI-S-AS domain scores at 
baseline and CGI-I-AS at Week 12 will also be explored.  
 
 
The sleep diary endpoints will be analyzed as continuous outcome variables. An average of daily
values for each sleep diary endpoint will be calculated for the 7 consecutive days prior to each  
visit when sleep diaries are collected. An MMRM ANCOVA methodology will be applied to the 
change from baseline endpoint as described previously.  
 
 
 
 
 
endpoint as described previously.
scale, an ANCOVA methodology will be applied to the change from baseline to Week 12
used to analyze the change from baseline in CSHQ score.
variable. An MMRM ANCOVA methodology similar to the one described previously will be
actigraphy v


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7.8.5 Description of Subgroups to be Analyzed 
Descriptive statistics will be presented separately by age group (randomization stratification 
variable: age 4 to 8 years versus age 9 to 12 years) for the primary endpoint and the two key 
secondary endpoints. Observed values will be reported by treatment group. The difference in 
means or proportions for OV101 versus placebo groups will also be presented with the 
corresponding 95% confidence intervals. Similar subgroup analysis will be conducted for region 
(US versus outside US). 
 
If for a given endpoint, the results in the 2 subgroups appear different from a clinical perspective, 
the appropriate model (MMRM, GEE, or logistic) could be constructed as described above, 
including an age-by-treatment interaction term. This interaction term will be tested at alpha level 
of 0.10 to assess whether the treatment effects are statistically different for the 2 age subgroups. 
 
7.9 Safety Analyses 
All safety analyses will be based on the SS. Descriptive statistics will be used to summarize all 
safety endpoints by treatment group. Two-sided 95% CIs will be presented where meaningful. 
Data summaries will be displayed for incidence of AEs, clinical laboratory variables, vital signs, 
body weight and body mass index, physical examinations, clinical assessment of suicidality, and 
seizure diary data. 
 
Unless otherwise specified below, safety data for subjects 2 to 3 years old (inclusive) will only 
be presented in listings and will be displayed in by-subject graphs, as appropriate. 
 
7.9.1 Adverse Events 
All TEAEs will be coded using MedDRA and will be summarized by MedDRA system organ 
class and preferred term and treatment group. Detailed listings of TEAEs, SAEs, related AEs, 
and discontinuations due to AEs will be provided. 
 
The incidence of TEAEs, discontinuations due to TEAEs, drug-related, and serious TEAEs will 
be summarized. Incidence of TEAEs by severity and relationship to study drug will also be 
presented. 
 
Incidence of TEAEs will be summarized separately for subjects 2 to 3 years old (inclusive). 
 
7.9.2 Clinical Laboratory Tests 
Changes from baseline to each post baseline visit with respect to clinical chemistry and 
hematology results will be summarized descriptively. Each laboratory parameter will be 


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classified as low, normal, or high relative to the parameter’s reference range and will be 
summarized with shift tables. Listings of subjects with abnormal results will be provided. 
 
7.9.3 Vital Signs and Physical Examinations 
Vital signs (systolic and diastolic blood pressure, temperature, heart rate, and respiratory rate), 
weight, and body mass index will be summarized descriptively at baseline and all post baseline 
study visits by treatment group. Change from baseline to all post baseline study visits will be 
summarized descriptively by treatment group. 
 
Physical examinations (general appearance; skin; head, ears, eyes, nose, and throat; neck; lymph 
nodes; chest (including lungs); heart; abdomen; extremities; nervous system; and 
musculoskeletal system) at baseline will be summarized. Shifts from baseline to post baseline 
study visits in each body system/site will be summarized by treatment group. 
 
7.9.4 Suicidality 
Suicidality assessed by ABC-I will be summarized descriptively at baseline and all post baseline 
study visits by treatment group. Change from baseline to all post baseline study visits also will 
be summarized descriptively by treatment group. 
 
7.9.5 Seizure Diary Data 
Seizure diary data will be summarized descriptively at baseline and all post baseline study visits 
by treatment group. Additionally, the seizure frequency (expressed as a 28-day frequency) will 
be calculated for the following study periods: Baseline (Screening to Day 1), Week 6 (Day 1 to 
Week 6 visit date), and Week 12 (Week 6 visit date + 1 to Week 12 visit date). Percent change in 
seizure frequency from baseline to all post baseline study visits also will be summarized 
descriptively by treatment group. 
 
7.10 Other Analyses 
7.10.1 Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) and will be summarized according to their WHO-DD Anatomic Therapeutic 
Chemical class level 4 and preferred drug name within Anatomic Therapeutic Chemical class 
level 4. The number and percentage of subjects who took at least 1 medication post baseline as 
well as the number and percentage of subjects who took each type of medication will be 
presented for each treatment group. 


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The PK data set will be used for all PK analyses.
At the end of the study, OV101 concentration and time data obtained from this study will
The population PK OV101 plasma exposure parameters will be further evaluated using a PBPK
OV101 plasma concentrations will be summarized descriptively at each timepoint. The
The population PK-derived exposure estimates (Cmax and AUC) and other parameters (if derived)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.11 Interim Analyses 
No interim analyses of efficacy data are planned for this study. 
 
7.12 Statistical Testing and Significance Level 
The primary analysis will be performed on the FAS and the PPS. However, the PPS analysis will 
only be considered a sensitivity analysis. 
 
Inferential treatment comparison of the primary efficacy endpoint, CGI-I-AS at Week 12, will be 
conducted at the 0.050 level of significance using a 2-tailed test. If the null hypothesis of no 
presented.
will be summarized descriptively and geometric means and coefficients of variation will be
missing.
variation. Plasma concentrations below the lower limit of quantification will be treated as
descriptive statistics to be presented will include geometric mean and geometric coefficient of
may also be estimated.
separately. In addition to Cmax and AUC exposure estimates, elimination half-life and tmax values
as age-related hepatic, and renal function estimates). The PBPK modeling details will be reported
organ size, blood flow, tissue perfusion, protein binding, transporter/enzyme expression as well
pediatric anatomy, developmental and physiologic data (including body weight, composition,
distribution, metabolism, and excretion data as well as appropriate age -specific adult and
simulations are based upon known OV101-related physicochemical, formulation, and absorption,
platform applied to extant PK data from adult and adolescent subjects. The PBPK model and
model specific for OV101 that was developed using a commercially available PBPK software
pediatric study population 2 to 12 years old at various weight bands.
evaluated using validated PBPK modeling to confirm predicted exposure estimates for the
subsequently be subjected to population PK modeling and resulting exposure estimates will be
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treatment difference for the primary endpoint is rejected, the alpha (0.05) will be passed to the 
significance testing for the key efficacy endpoints, CGI-I-AS response (at least minimally 
improved) at Week 12 and CGI-I-AS response (at least much improved) at Week 12, which will 
be tested using the corresponding 2-sided tests at 0.05 level of significance in a fixed sequence. 
If and only if the null hypothesis of no treatment difference based on CGI-I-AS response (at least 
minimally improved) is rejected at 0.05 level of significance, testing will continue and the null 
hypothesis of no treatment difference based on CGI-I-AS response (at least much improved) will 
be tested at 0.05 level of significance. 
 
No formal statistical testing of other secondary endpoints will be performed. All P values 
presented for secondary and tertiary endpoints will be considered descriptive in nature. 
 
7.13 Missing Data Handling and Sensitivity Analysis 
The MMRM model used in the analysis of key efficacy endpoints implicitly adjusts for missing 
data. If missing data are 5% or more for the primary endpoint, a sensitivity analysis will be 
performed, with missing outcomes be imputed in the analysis models. Multiple imputation 
techniques will be used for imputation, under the assumption of data missing not at random. 
Additionally, a tipping point analysis will be performed. Details will be specified in the SAP. 
 
Rules for imputation of missing dates for AEs and concomitant medications will be stated in the 
SAP. 


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8 
Data Quality Assurance 
This study will be conducted according to the International Council for Harmonisation (ICH) E6 
(R2) risk and quality processes described in the applicable procedural documents. The quality 
management approach to be implemented in this study will be documented and will comply with 
the current ICH guidance on quality and risk management. 
 
Standard operating procedures are available for all activities relevant to the quality of this study. 
Designated staff will be responsible for implementing and maintaining quality assurance and 
quality control systems to ensure that the study is conducted and that data are generated, 
documented, and reported in compliance with the study protocol, Good Clinical Practice (GCP), 
and Good Laboratory Practice requirements as well as applicable regulatory requirements and 
local laws, rules, and regulations relating to the conduct of the clinical study. 
 
An authorized quality assurance auditor will audit the study data and procedures at periodic 
intervals as indicated. Domestic or foreign regulatory authorities, the IRB or IEC, and a Sponsor- 
authorized auditor may request access to all study documentation for an on-site inspection or 
audit. The investigator must notify the Sponsor of any regulatory authority inspections and 
forward copies of the inspection report to the Sponsor. 
 
Electronic data systems will be in accordance with applicable aspects of US Title 21 Code of 
Federal Regulations (CFR) Part 11, ICH Guidelines, GCP, local laws and legislation, and the 
Health Insurance Portability and Accountability Act. 
 
8.1 On-Site Audits 
At any time, quality assurance representatives of the Sponsor and/or regulatory bodies may visit 
the unit to carry out an audit of the study in compliance with regulatory guidelines and company 
policy. Such audits will require access to study records, documentation, and regulatory files. At 
all times, subject privacy will be of utmost importance and maintained. Typically, sufficient 
(minimum of 2 weeks) notice will be given to the investigator to prepare for the visit. 
 
8.2 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include such documents as questionnaire 
results, sleep diaries, and computerized or otherwise automated assessments (e.g., actigraph). 
sleep diaries, 
(e.g., actigraph).


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Investigative site staff will enter subject data into Medidata RAVE® (the eCRF program). The 
analysis data sets will be a combination of these data and data from other sources (e.g., 
laboratory data). 
 
Clinical data management will be performed in accordance with applicable Sponsor standards 
and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data. Adverse event terms will be coded using MedDRA, an internal 
validated medical dictionary, and concomitant medications will be coded using the World Health 
Organization Drug Dictionary. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary. 
 
After database lock, each study site will receive a CD-ROM containing all its site specific eCRF 
data as entered into the EDC system for the study, including full discrepancy and audit history. 
Additionally, a CD-ROM copy of all the site’s data from the study will be created and sent to the 
Sponsor for storage. PPD will maintain a duplicate CD-ROM copy for their records. In all cases, 
subject initials will not be collected or transmitted to the Sponsor. 
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9 
Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human subjects in research studies. Before study onset, the protocol, 
informed consent, assent, advertisements to be used for the recruitment of study subjects, and 
any other written information regarding this study to be provided to the subject or the subject’s 
legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and 
of the IRB/IEC compliance with ICH harmonised tripartite guideline E6 (R2): GCP will be 
maintained by the site and will be available for review by the Sponsor or its designee. 
 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted. 
 
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator 
must promptly supply the Sponsor or its designee, the IRB/IEC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to subjects. 
 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
 
9.3 Subject Information and Consent 
A written informed consent in compliance with applicable regulatory authority regulations shall 
be obtained from the LAR/caregiver of a minor before the subject enters the study or any unusual 
or nonroutine procedure that involves risk to the subject is performed. For minors an assent 
document will be presented, and assent will be obtained before the subject participates in any 
study procedure. Informed consent and assent template documents may be provided by the 
Sponsor to investigative sites. If any institution-specific modifications to study-related 
procedures are proposed or made by the site, the consent and assent should be reviewed by the 
Sponsor or its designee or both before IRB submission. Once reviewed, the consent and assent 
will be submitted by the investigator to his or her IRB for review and approval before the start of 
the study. If the ICF is revised during the study, all active participating subjects and 
LAR/caregivers (as applicable) must sign the revised forms. 


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Before recruitment and enrollment, each prospective subject’s LAR/caregiver and subject (as 
applicable) will be given a full explanation of the study and will be allowed to read the approved 
ICF/assent. Once the investigator is assured that the LAR/caregiver and subject understand the 
implications of participating in the study, the LAR/caregiver and subject will be asked to give 
consent/assent to participate in the study by signing/approving the ICF/assent. 
 
The investigator shall retain the signed original ICFs/assents and give copies of the signed 
original forms to the LAR/caregivers and subjects, as applicable. 


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10 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments. 
 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the subject (or the subject’s legal guardian or LAR/caregiver), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the US Food and Drug Administration 
(FDA) or other applicable regulatory agency, or the IRB/IEC. 
 
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
 
10.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required under 21 CFR 
54. In addition, the investigator must provide to the Sponsor a commitment to promptly update 
this information if any relevant changes occur during the study and for 1 year following the 
completion of the study. 
 
Neither the Sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the Sponsor nor PPD is financially responsible for further 
treatment of the subject’s disease.  
 
10.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6 (R2) 8.2 and 
Title 21 of the CFR by providing essential documents, including but not limited to the following: 
PPD 
PPD i


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 IRB/IEC approval. 
 Original investigator-signed investigator agreement page of the protocol. 
 Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572. 
 Curriculum vitae for the investigator and each sub investigator listed on Form FDA 1572. 
 Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, the 
investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
 IRB/IEC-approved informed consent and assent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that is to 
be provided to the subject or legal guardian. 
 Laboratory certifications and normal ranges for any local laboratories used by the site, in 
accordance with 42 CFR 493. 
10.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH E6 
(R2). The investigator will conduct all aspects of this study in accordance with all national, state, 
and local laws or regulations. Study information from this protocol will be posted on publicly 
available clinical trial registers before the enrollment of subjects begins. 
 
10.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6 (R2) and all applicable guidelines and regulations. 
 
10.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs to the Sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the Sponsor and regulatory authority(ies) with any reports required. 


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10.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor. It is the responsibility of the Sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. 
 
10.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the Sponsor will be responsible for these 
activities and will work with the investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The Sponsor has final approval authority over all such issues. 
 
The data are the property of the Sponsor and cannot be published without prior authorization 
from the Sponsor, but data and publication thereof will not be unduly withheld. 


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11 Study Management 
11.1 Monitoring 
11.1.1 Independent Data Monitoring Committee 
An IDMC will monitor the study (Section 6.5): it will include 3 independent representatives 
including a chairperson, a pediatric epileptologist, and a biostatistician. The IDMC charter 
includes the details for the IDMC including responsibilities, qualifications, and key processes. 
The IDMC responsibilities will include (but are not limited to) the following: 
 
x Staged Enrollment Review Meetings. Subject assignment to treatment will be stratified 
and staged by age and gated by the IDMC via the evaluation of sentry subjects 
(Section 5.1). No age cohort may begin treatment without IDMC review of tolerability 
and PK in sentry subjects in the previous older cohort. 
 
x Meet periodically to review aggregate and individual subject data related to safety, data 
integrity, and overall conduct of the trial. 
 
x Work with the Independent Statistical Center to determine the data presentations (tables, 
listings, and figures) that are necessary for the IDMC to monitor study conduct and 
safety. 
 
x Review and evaluate the content of all data presentations received before each IDMC 
Meeting. 
 
x Contribute to closed session reviews and recommendations. 
 
11.1.2 Clinical Trial Steering Committee 
The CTSC will include approximately 5 independent representatives, including a chairperson, 
representatives with relevant expertise in pediatric psychiatry, pediatric epileptology, pediatric 
neurology and psychology, and a parent of a child with AS. In addition, 2 Sponsor 
representatives will be included on the CTSC. The CTSC responsibilities will include (but are 
not limited to) the following: 
 
x Conduct interim review of the trial’s progress including updated data on recruitment and 
data quality. 
 
x Review recommendations of the IDMC including but not limited to: 
and PK i


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o Safety issues which may suggest risk to currently enrolled or future subjects 
 
o Recommendations to modify or terminate the trial if, following review of the data, 
there are safety or efficacy concerns. 
 
 Monitor compliance with IDMC recommendations. 
 
 Monitor recruitment data and accrual within relevant subsets, screen failures, dropouts, 
and losses to follow-up overall and by study site. 
 
 Monitor compliance with the protocol and protocol violations by subjects and 
investigators. 
 
 Advise on protocol modifications suggested by investigators or Sponsors (e.g., 
amendments to inclusion criteria, trial endpoints, or sample size). 
 
 Monitor planned sample size assumptions. 
 
 Monitor continuing appropriateness of subject information. 
 
 Assess the impact and relevance of external evidence. 
 
11.1.3 Monitoring of the Study 
The clinical monitor, as a representative of the Sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the investigator and study site at periodic intervals, in 
addition to maintaining necessary telephone and letter contact. The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and personnel. 
 
All aspects of the study will be carefully monitored, by the Sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
 
11.1.4 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow the Sponsor, representatives of the Sponsor, or 
a regulatory agency access to all study records. 


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The investigator should promptly notify the Sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the Sponsor. 
 
11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, must be reviewed and approved by the Sponsor or its designee. 
Amendments to the protocol must be submitted in writing to the investigator’s IRB/IEC for 
approval before subjects can be enrolled into an amended protocol. 
 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the subject’s source documentation 
any deviation from the approved protocol. The investigator may implement a deviation from, or 
a change of, the protocol to eliminate an immediate hazard to study subjects without prior 
IRB/IEC approval. As soon as possible after such an occurrence, the implemented deviation or 
change, the reasons for it, and any proposed protocol amendments should be submitted to the 
IRB/IEC for review and approval, to the Sponsor for agreement, and to the regulatory 
authorities, if required. 
 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the IRB/IEC and agreed to by the investigator. A 
significant deviation occurs when there is nonadherence to the protocol by the subject or 
investigator that results in a significant, additional risk to the subject. Significant deviations can 
include nonadherence to inclusion or exclusion criteria, or nonadherence to FDA regulations or 
ICH GCP guidelines, and will lead to the subject being withdrawn from the study (Section 4.2). 
 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of deviations. 
The IRB/IEC should be notified of all protocol deviations in a timely manner. 
 
11.3 Study Termination 
Although Ovid has every intention of completing the study, Ovid reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 
 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes the phone EOS visit). 
PPD 


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11.4 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study reports (CSRs) are prepared and provided to the regulatory agencies as required by 
the applicable regulatory requirements. The Sponsor will also ensure that the CSRs in marketing 
applications meet the standards of the ICH harmonised tripartite guideline E3: Structure and 
content of CSRs. 
 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
 
Upon completion of the CSR, the Sponsor will provide the investigator with the full summary of 
the study results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. The study results will be posted on publicly available clinical trial 
registers. 


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12 Reference List 
 Berry JA, Cervantes-Sandoval I, Chakraborty M, et al. Sleep facilitates memory by 
blocking dopamine neuron-mediated forgetting. Cell. 2015; 161(7):1656-67. 
 
 Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and 
implications for disease. Neuron. 2012; 73(1):23-34. 
 
 Deidda G, Bozarth IF, Cancedda L. Modulation of GABAergic transmission in 
development and neurodevelopmental disorders: investigating physiology and pathology 
to gain therapeutic perspectives. Front Cell Neurosci. 2014; 8:119. 
 
 Dissel S, Angadi V, Kirszenblat L, et al. Sleep restores behavioral plasticity to Drosophila 
mutants. Curr Biol. 2015; 25(10):1270-81. 
 
 Egawa K, Fukuda A. Pathophysiological power of improper tonic GABA(A) 
conductances in mature and immature models. Front Neural Circuits. 2013; 7:170. 
 
 Egawa K, Kitagawa K, Inoue, K, et al. Decreased tonic inhibition in cerebellar granule 
cells causes motor dysfunction in a mouse model of Angelman syndrome. Sci Transl 
Med. 2012;4(163):163ra157. 
 
 Hodges JL, Lehmann EL. Estimation of location based on ranks. Annals Mathematical 
Statistics. 1963; 34 (2):598–611. 
 
 Howie SRC. Blood sample volumes in child health research: review of safe limits. 
Bulletin of the WHO. [Internet] 2011 [cited 24 May 2019]; 89(1):46-53. Available from: 
https://www.who.int/bulletin/volumes/89/1/BLT-10-080010-table-T2.html. 
 
 Merck. Study # 027: A placebo-controlled, double-blind, multiple dose safety, tolerability 
and pharmacokinetic study of Lu 02-030 following sequentially escalating doses in 
healthy young men and at one dose level in healthy young women and healthy elderly. 
2001 
 
 Merck. Study # P031: A 2-part study to assess the tolerability of gaboxadol (MK-0928) 
administered intravenously (Part 1) and a 6-period crossover to examine the dose 
proportionality of 5 single oral doses of MK-0928 in the range of 2.5 to 20 mg 
administered over periods 1 through 5 followed by a fixed sequence, open IV arm (period 
6) in healthy young adult male and female subjects (Part 2). 2006. 


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x
Owens JA, Spirito A, McGuinn M. The Children's Sleep Habits Questionnaire (CSHQ):
and adolescents with cerebral palsy: hearing the voices of the children. Dev Med Child
preliminary reliability and validity. Health Qual Life Outcomes. 2004:2:55.
x Mertz LG, Christensen R, Vogel I, et al. Angelman syndrome in Denmark. Birth 
incidence, genetic findings, and age at diagnosis. Am J Med Genet A. 2013; 161A (9): 
2197-2203. 
x Ovid Therapeutics Inc. Gaboxadol (OV101). Investigator’s Brochure, 3rd ed. New York 
(NY); 2018. 87 p. 
x Ovid Therapeutics Inc. (New York, USA). OV101-16-001: A phase 1 single dose PK 
study in adolescent subjects with Fragile X syndrome or Angelman syndrome. 2018. 
 
 
 
x Petersen MB, Brondum-Nielsen K, Hansen LK, et al. Clinical, cytogenetic, and 
molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish 
county. Am J Med Genet. 1995; 60:261-2. 
 
x Ramamoorthi K, Lin Y. The contribution of GABAergic dysfunction to 
neurodevelopmental disorders. Trends Mol Med. 2011; 17(8):452-62. 
 
x Sparrow SS, Cicchetti DV, and Balla DA. Vineland II: Vineland Adaptive Behavior 
Scales. Circle Pines, MN, American Guidance Service 2005. 
 
x Sparrow SS, Cicchetti DV and Saulnier CA. Vineland Adaptive Behavior Scales, third 
edition (Vineland-3). Circle Pines, MN, American Guidance Service. 2016. 
 
x Steffenburg S, Gillberg CL, Steffenburg U, et al. Autism in Angelman syndrome: a 
population-based study. Pediatr Neurol. 1996; 14(2):131-136. 
 
x


x

x Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated 
consensus for diagnostic criteria. Am J Med Genet A. 2006; 140(5):413-8. 
Neurol. 2005; 47(9):592-7.
23(8):1043-51.
psychometric properties of a survey instrument for school-aged children. Sleep. 2000;
Varni JW, Sherman SA, Burwinkle TM, et al. The PedQoLI™ Family Impact Module:
Varni JW, Burwinkle TM, Sherman SA, et al. Health-related quality of life of children
Family Impact Module:
™
Varni JW, Sherman SA, Burwinkle TM, et al. The PedQoLI™
x


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13 Pandemic Addendum 
The purpose of this addendum is to safeguard the safety of study subjects, ensure continuation of 
study conduct, and preserve the integrity of the study, in case of a general public health crisis or 
pandemic such as COVID-19. This addendum addresses situations in which scheduled in person 
clinic visits are not feasible due to local, regional or national restrictions. 
Specifically, the addendum aims to ensure: 
 Continued safe study conduct and participation of existing patients
 Uninterrupted supply of study treatment
 Integrity of data capture and minimization of missing data
Written communication from sponsor Medical Advisor or Clinical Operations Lead is required 
before any portion of this addendum is put into effect. The communication shall be documented 
and captured in the Trial Master File. 
The Principal Investigator, holds the ultimate responsibility for the safety and well-being of 
study subjects and as always, shall maintain compliance with the current local and health 
authority guidelines and recommendations pertaining to the pandemic. 
This guidance is categorized below by the different stages of subject participation in the 
NEPTUNE study: 
 
Guidance for subjects scheduled to undergo study screening 
 For subjects 4-12 years old who are unable to attend a clinic visit in person
o Remote screening via telehealth and/or telephone may be performed at the discretion 
of the Principal Investigator. The choice of telehealth platform is the Principal 
Investigator’s discretion but must be consistent with local policies and standard 
practice. The requirements for data protection, must be adhered to. 
o Informed Consent may be sent to the subject either electronically (pdf format) or by 
mail prior to the scheduled screening visit 
o Informed consent can be performed via telehealth or telephone during the screening 
visit and documented in the source document with the date and time of the verbal 
consent. Wet ink signature on ICF should be returned to the site via courier. 


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and Sleep diary
x For remote screening
o Site must ensure that subject has access to a weighing scale, for determination of 
weight band assignment 
o Screening visit clinical labs may be performed at a local laboratory. Reference ranges 
must be documented 
o Home visits may be conducted by a trained mobile healthcare professional to perform 
study assessments e.g. vital signs, body weight assessment, clinical lab draws, 
review/collection of study materials 
o Instructions should be provided verbally or in writing to the caregiver 
o 
 
o 
 
o Copies of Seizure 
forms should be sent to caregiver. Electronic 
copies may be provided if caregivers can make physical copies. 
o Pre-paid envelopes will be provided to support the shipping of the diaries 
o Update EDC as soon as possible to allow planning of IP shipment 
o Notify Sponsor/CRA to plan support with shipment arrangement 
x For subjects 2-3 years old
o Screening shall be performed on-site. If pandemic restrictions preclude on-site visits, 
then screening of subjects 2-3 yrs old shall be placed on a temporary hold until 
permissible under local and investigative site’s guidelines 
o Informed Consent may be sent to the subject either electronically (pdf format) or by 
mail prior to the scheduled screening visit. The signed consent should be returned by 
the subject to the site and appropriately filed. If Informed Consent is completed 
remotely, a wet ink signature on ICF should be returned to the site via courier. 
Guidance for subjects scheduled for Randomization/Baseline Visit 
x Randomization visits can only occur when patients can physically be present on-site
x If the baseline visit cannot be conducted within 28 days of screening, it should be captured as 
a protocol deviation due to pandemic restrictions but do not automatically screen fail the 
subject. IWRS and EDC will not automatically screen fail subjects in this case
x Every attempt should be made to follow procedures at the randomization visit as per study 
protocol. Any deviation should be appropriately documented and reported to each site’s 
IRBs/ECs per their reporting guidelines
x Additional instructions pertaining to the randomization visit will be provided for subjects 
who are still in the screening phase when pandemic restrictions are scaled back, and subjects 
are able to attend clinic visits in person
Caregivers should contact the site team promptly should they have any questions or 
concerns pertaining to the actigraphy device or other study accessories. 
Actigraphy devices, related accessories including charging equipment, data hub, 
bands, and instructions should be sent to subject from the site via courier. 


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remotely
actigraphy website portal. Resetting monitoring period for actigraphy device can be done
monitor the compliance of sleep data collection from the actigraphy device, as usual via the
subject’s possession if the family cannot travel to site. However, the site staff should closely
The actigraphy device may remain in the
x 

x IP will be provided to subject at the site
x 

x Seizure and sleep diaries must be collected and reviewed as per protocol procedures and 
Epilepsy Consortium instructions including SIF and DRF forms. Physical/electronic PDF 
copies of diaries (including medication diary) should be provided in preparation of week 6 
and week 12 visits
x Preprinted shipment labels and envelopes should be provided to caregivers to receive diaries
x Upon retrieval of diaries, EDC should be updated accordingly
Guidance for established subjects completing Week 6 Study Visit 
x 
Schedule the visit as close as possible to Week 6 date to allow time to ship IP.
x When on-site visits are not feasible, remote assessment of the CGI-I-AS, CGI-S-AS, VABS3, 
and other PROs) may be performed via your institution-approved (HIPAA compliant) 
telehealth system. Telehealth assessments must be consistent with local policies and 
standards. The requirements for data protection of Personal Health Information (PHI) must 
be adhered to.
x In the absence of a telehealth system, a remote assessment is to be completed by utilizing a 
unified communication software such as Skype, Microsoft Teams or Zoom
x Provide a script to a local lab as required per clinical labs per protocol
x Home visits may be conducted by a trained mobile healthcare professional to perform study 
assessments e.g. vital signs, body system assessment, clinical labs draws, review/collection 
of study materials
x If the site visits become possible/permissible at any point between Week 6 and Week 12, the 
subject should be scheduled for an on-site, unscheduled visit prior to week 12 time point and 
all safety assessments should be completed at this visit
x IP with kit number will be assigned to each subject. Where allowed, a preferred courier will 
be assigned to pick up and deliver the IP to subject.
 
 
 
 
 
 
Guidance established subjects completing Week 12 Study Visit 
x Whenever possible, all week 12 visits should be completed onsite
x If an onsite visit is not possible, a remote visit should be completed to collect assessments via 
telehealth system. A unified communication software such as Skype, Microsoft Teams or
should they need to reset sleep monitoring period via Actigraph
Caregivers must be instructed that they need to contact site staff at their earliest convenience,
non-collection must be documented.
PK lab draw collections should be performed where possible. If not collected, the reason for
and sleep 


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Zoom may be utilized unless prohibited by local guidelines. Telehealth assessments must be 
consistent with local policies and standards. The requirements for data protection, must be 
adhered to. 
x Provide a script to a local lab for clinical labs required per protocol
x Home visits may be conducted by a trained mobile healthcare professional to perform study 
assessments e.g. vital signs, body system assessment, clinical labs draws, review/collection 
of study materials
x For subjects intending to immediately transition into ELARA, the week 12 (NEPTUNE 
EOT) visit may be considered as ELARA Baseline if ELARA protocol criteria are met.
x Unused IP should be shipped back to site for reconciliation. 
x 


x Ensure subject diaries are collected and reviewed appropriately.
x If any patient is enrolling into the ELARA study immediately after week 12 visit, EOS week 
14 visit (over the phone) should be completed prior to enrollment into ELARA
If at any time during the conduct of the NEPTUNE study /a subject contracts COVID-19 
infection or any reportable infectious disease, the local health authority requirements regarding 
treatment/reporting/quarantine should be followed. The event should be reported as an AE/SAE 
and the investigator should determine if study treatment should be continued, temporarily 
interrupted, or discontinued. 
your site.
successfully and provide shipping label to caregivers to send the actigraphy device back to
Ensure sleep data collection via actigraphy device for week 12 has been collected

SAP_001.pdf: 
 
A MulticeNter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Phase 3 Study to Evaluate the Efficacy and Safety of OV101 in PediaTric 
IndividUals with AngelmaN SyndromE (NEPTUNE) 
 
OV101-19-001 
Ovid Therapeutics Inc. 
 OV101-19-001 
 
 
 
 
 
 
 
 
 
 
 
 
OVID THERAPEUTICS INC. 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
SAP Version: 
Date of Statistical Analysis Plan: 
 
Version 3.0 
15Oct2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAP Version 3.0: 15Oct2020 
Page 1 of 68 


19-OCT-2020
 
 
Ovid Therapeutics Inc. 
 OVl 01-19-001 
 
 
 
SIGNATURE PAGE 
 
 
 
 
15-0oc-ioz,,o 
Date 
Biostatjstician ll, PROMETRlKA 
 
 
 
Pr 
Manager, Bi.ostatistics, PROMETRIKA 
 
 
\ f,  -  OC:T - 02'0 (/7. S 
 
 
Date 
-R-ev-=i-ew-ed_b_yM_:i_,g  ,,_11_u_s_h_S_te_p_a-,1-ia_n_s , P _
__o
h _   
 
President and Chief Executive Officer, PROMETRJKA 
Senior Statistical Advisor 
 
 
 
 
 
Date 
Revi wed and Approved by: Ying Yan, Ph.D. 
Vice Pr s\pent, Biostatistics, Programming & Data 
Manapement 
Ovid therapeutics Inc.  
 
 
 
 
Date 
 Reviewed and Approved by: 
Mathews Adera, M.D. 
Vice President, Neurodevelopment 
Ovid Therapeutics inc. 
 
 
 
 
 
SAP Version '.LO: 15Oct2020 
Page 2 of 68 
19 OCT 2020
 
 
Prepared by: Chris olcroft, Sc.D.
y: Chris
lcroft
ol
Sc D


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DOCUMENT HISTORY 
 
Version
Author 
Description 
1.0 
Christina
New Document 
 
 
Holcroft;  
 
 
Miganush  
 
 
Stepanians;  
 
Shijie Chen  
 
(Reviewer)  
 
2.0 
 
Updates that follow the protocol amendment are noted at 
Miganush  
 
Stepanians;
the end with text “(Amendment)”.  
 
 
er on Version 1.0. 
Christina  
x
Added Shijie Chen as a review
 
Holcroft;  
x
Section 1: Removed prior proto ol version. 
 
Linda  
x Section 2.1: Added key secondary objectives and 
 
Huang  
changed heading of original secondary objectives to 
 
(Reviewer)
“Other Secondary Objectives”. (Amendment) 
x Section 2.2: Removed Week 14 follow up phone visit. 
(Amendment) 
x Section 2.2.1: Increased total number of subjects to 90 
and number of subjects per treatment group to 45. 
Increased number of study sites to 15. (Amendment) 
x Section  2.2.2:  Added  randomization  stratification 
 
 
 
 
category
of 
region, 
US 
versus 
outside 
US. 
 
 
 
(Amendment)  
 
 
x
Section 3.1.3: Updated to desc 
primary efficacy endpoint and
efficacy endpoints. 
ribe statistical testing for 
new key secondary 


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data imputation analysis because it is now an
exploratory endpoint.
x
Section 3.3.2: Added key secondary efficacy variables.
(Amendment)
x
Section 3.3.3: Specified original secondary variables as
“Other Secondary” (Amendment). Moved actigraphy
total daytime sleep variable to exploratory variables.
exploratory variables. Renamed Peds QL™ endpoints
to follow precise language in the manual.
efficacy variables to reflect that derivations for these
actigraphy variables are exploratory for this subject
population. Also changed language for variables to that
it is not specific to a particular vendor.
screening and region. Specified weight at baseline. 
x
Section 3.5: Added clarification for date imputation.
Specified rescue and anti-epileptic medications.
x
Section 3.6.1: Specified SS and FAS. Corrected weight
band from baseline to screening. Specified that expected
capsules will utilize the titration schedule and down
titrations, following protocol language. Added that
programming specifications.
x
Section 3.6.2: Added FAS.
 
 
x


x





x Section 3.3.4: 
 
 
x Section 3.3.5: 
 
 
 
 
x 







in 
 
 
Created new section for exploratory
Moved actigraphy daily activity level to
Section 3.2.2: Added region to subgroups.
complete derivation details will be provided
Section 3.4.1: Added FAS and PPS. Added age at
Section 3.1.6.1: Removed daytime sleep from missing
complete derivation details will be provided
Section 3.4.1: Added FAS and PPS. Added age at
Section 3.2.2: Added region to subgroups.
Moved actigraphy daily activity level to
Created new section for exploratory
Section 3.1.6.1: Removed daytime sleep from missing


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MMRM analysis, specified that REML will be used.
Additionally, the Kenward-Roger adjustment will be
used with an unstructured covariance and a sandwich
estimator will be used for a structured covariance.
x
Section 3.7.2: Created new section for key secondary
endpoint analysis.
x
Section  3.7.3:  Added  region  to  analysis  models.
Removed actigraphy total daytime sleep variable from
this section because it is now an exploratory variable.
that subgroup analysis will be conducted for primary
and two key secondary endpoints. Adjusted the section
to be specific to the analysis of these endpoints.
x
Section 3.7.6: Added region to analysis models.
x
Section 3.8.1.2: Included tables for SOC/HLGT/PT and
x
Section 4.1.2: Added specification about actigraphy
variable  derivations.  Removed  language  that  was
specific to a particular vendor.
 
 
x 









Made updates to MMRM analysis as done in Section 
3.7.1.  
 
x 
 
 
 
 
 
 
 
 
 
/
  
 
  


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x Section 4.1.6: Added Peds QL™ version. 
x Section 4.2.2: Added age at screening. 
x Section 5.1: Updated SAS code to match updated 
analysis text. Added sample SAS code for GEE 
analysis. 
x References: Deleted BSSR reference, Gould and Shih 
(1992). Added Aman et al. (1985). 
 3.0 
Suzanne 
Granger; 
Christina 
Holcroft; 
Miganush 
Stepanians;
Ying Yan 
(Reviewer) 
Yinpu Chen 
(Reviewer) 
x Section 1: Added COVID-19 language. 
x Section 2.1: Added to follow the protocol: “The 
purpose of the key secondary objectives is to fulfil a 
recommendation of the EMA for a responder analysis.” 
x Section 2.2.1: Changed from “up to” to “approximately” 
5 subjects 2 to 3 years old. 
x Section 2.2.4: Added SAE reporting requirements. 
x Table 1: Updated Schedule of Activities to follow 
protocol version 4. 
x Sections 3.1.2 & 3.6: Replaced “patients” with 
“subjects”. 
x Section 3.1.4: Added specificity to the baseline 
definition for assessments collected on Day 1 after the 
administration of first dose. 
x Section 3.1.7: Changed from “descriptive analysis will 
be performed by site and country” to “… performed by 
country”. 
x Section 3.1.8: Added new section for Analysis Visit 
Windows. 


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x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
x 
 
x 
 
 
 
 
x 
 
 
 
x 
 
x 
Section 3.2.1: Expanded the Intent-to-treat and Safety 
Set to include 2-3 year old subjects. For the Full 
Analysis  Set,  specified  that  the  primary  efficacy 
endpoint is defined as CGI-I-AS at Week 6 or Week 12. 
For the Per Protocol Set, specified that subjects need to 
complete the Week 12 CGI-I-AS. For the Safety Set, 
changed that it will consist of all “randomized subjects” 
to “subjects in the ITT”. Specified that safety analyses 
will be conducted separately for subjects 2 to 3 years old 
(inclusive) and subjects 4 to 12 years old (inclusive).  
Sections 3.3.1 – 3.3.7: Added “endpoint” term to the 
section headers.
Section 3.3.2: Added “The key secondary endpoints will 
be utilized to fulfill a recommendation of EMA for a 
responder analysis.”  
Section 3.3.3: Added VABS-3 Total Score (Adaptive 
Behavior Composite Score) endpoint.
Section 3.3.5: Added ABC-C subscale scores for 
Lethargy/Social  Withdrawal,  Stereotypic  Behavior, 
Hyperactivity/Non-compliance,  
and  
Inappropriate 
Speech.  
Section 3.3.6: Removed “shift in physical examination 
parameters” because these parameters are not collected 
in the database.  
Section 3.4.1: Added summary details. Added COVID- 
19 summary analyses.  
Section 3.4.2: Added listing details.  
 


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x
 
x
 
 
x
x
 
 
 
 
 
 
 
 
 
 
 
 
 
x
x
 
 
 
 
 
 
 
 
x
Sections 3.5.1 – 3.5.3, 3.6.1 – 3.6.3: Added summary 
details.  
Section 3.1.6.1: Changed threshold for analysis of 
missing actigraphy endpoints from less than 30% to less 
than 20%.  
Section 3.7.1: Moved section and added summary 
details.  
Section 3.7.2: Changed section header to “Compliance 
to Protocol Intended Dose.”  In the “Total number of 
capsules taken” formula, removed total number of 
capsules not taken and not returned because this
information is not reported. Added that, “Total number 
of capsules taken will be missing if drug kit is dispensed 
but not returned or is lost.” In expected number of
capsules derivation, removed dosing based on down- 
titrations. Revised the compliance calculation to include 
capsule counts from the medication eDiary if the drug 
dispensation capsule counts are missing.  
Sections 3.8, 3.8.1 – 3.8.4: Added summary details.  
Section 3.8.1: Added summary of CGI-I-AS by method 
of assessment (on site vs. remote/phone visit). Revised 
the threshold for missing data imputation from more 
than 5% to more than 3% missing CGI-I-AS values at 
Week 12. Added supportive analysis for the CGI-I-AS 
MMRM ANOVA analysis for the FAS using alternative 
visit window mapping.  
Section 3.8.2: Replaced GEE approach with a
generalized logit model using PROC GLIMMIX in 
 


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weekday and weekend averages.
Added summary
analysis for ABC-C subscales.  
Section 3.8.6: Revised the threshold for missing data
sensitivity analyses based on method of assessment
collection (at least one CGI-I-AS assessment conducted
remotely or no CGI-I-AS assessment conducted
remotely). Added supportive analysis using alternative 
actigraphy to match the protocol and specified a
weighted average value calculation based on weekday
and weekend averages. Added VABS-3 Total Score
(Adaptive Behavior Composite Score) and subdomain
v-Scale scores analyses.
endpoint analysis. Revised the analysis visit windows
for sleep diary endpoints to match the protocol and
x
3% missing CGI-I-AS values at Week 12. Changed
threshold for analysis of missing actigraphy endpoints
from less than 30% to less than 20%.
x Sections 3.9.1.1 – 3.9.1.4, 3.9.2 – 3.9.4, 3.9.6: Added
summary details.
x
Sections 4.1.2 – 4.1.6: Added summary details and
assessment summary score algorithms.
x
Section 4.1.7: Added a section for ABC-I.
 
 
 
 
 
 
 
 
x 





x 
Section 3.8.4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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x Section 6: Removed section for List of Tables, Figures, 
and Listings because list is maintained outside of the 
SAP. 
 


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Table of Contents 
1
INTRODUCTION ................................................................................................18 
2 
STUDY SUMMARY ...........................................................................................18 
2.1
Study Objectives ............................................................................................18 
2.2
Study Design .................................................................................................20 
2.2.1
Number of Subjects ................................................................................20 
2.2.2
Randomization and Blinding Procedures ...............................................20 
2.2.3
Efficacy Assessments .............................................................................21 
2.2.4
Safety Assessments ................................................................................22 
2.2.5 
3 
STATISTICAL METHODS ................................................................................27 
3.1
General Methods ...........................................................................................27 
3.1.1
Computing Environment ........................................................................27 
3.1.2
Reporting of Numerical Values..............................................................27 
3.1.3
Statistical Testing and Significance Level .............................................27 
3.1.4
Baseline Value and Change from Baseline ............................................28 
3.1.5
Study Day ...............................................................................................28 
3.1.6
Handling of Missing/Incomplete Values ................................................28 
3.1.7
Methods of Pooling Data ........................................................................29 
3.1.8
Analysis Visit Windows .........................................................................29 
3.2
Analysis Populations and Subgroups .............................................................31 
3.2.1
Definition of Analysis Populations ........................................................31 
23


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3.3.4
Tertiary Efficacy Endpoints ...................................................................33
3.3.5
Exploratory Efficacy Endpoints .............................................................34
 
 
3.2.2
Definition of Subgroups .........................................................................32 
3.3
Analysis Endpoints ........................................................................................32 
3.3.1
Primary Efficacy Endpoint .....................................................................32 
3.3.2
Key Secondary Efficacy Endpoint .........................................................32 
3.3.3
Other Secondary Efficacy Endpoints .....................................................32 
 
 
 
3.3.6 
Safety Endpoints ................................................................................... 34 
 
3.3.7 
 
3.4
Subject Disposition and Evaluability .............................................................35 
3.4.1
Subject Disposition.................................................................................35 
3.4.2
Protocol Deviations ................................................................................36 
3.5
Demographics and Baseline Characteristics ..................................................36 
3.5.1
Demographics .........................................................................................36 
3.5.2
Medical History ......................................................................................37 
3.5.3
Seizure History .......................................................................................37 
3.6
Prior and Concomitant Medications ..............................................................37 
3.6.1
Non-Benzodiazepine Concomitant Medication .....................................38 
3.6.2
Benzodiazepine Concomitant Medication..............................................38 
3.6.3
Most Common Concomitant Medication ...............................................39 
3.7
Treatment Exposure and Compliance ............................................................39 
3.7.1
Exposure to Study Treatment .................................................................39 
35


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3.7.2
Compliance to Protocol Intended Dose ..................................................39 
3.8
Efficacy Analyses ..........................................................................................40 
3.8.1
Primary Efficacy Endpoint Analyses ......................................................41 
3.8.2 Key Secondary Efficacy Endpoint Analyses ..............................................43 
3.8.3 Other Secondary Efficacy Endpoint Analyses ...........................................44 
3.8.5 Subgroups to be Analyzed ..........................................................................47 
3.8.6 Missing Data Handling and Sensitivity Analysis .......................................47 
3.9
Safety Analysis ..............................................................................................50 
3.9.1
Adverse Events .......................................................................................51 
3.9.2
Clinical Laboratory Evaluation ..............................................................54 
3.9.3
Vital Signs and Other Physical Findings ................................................54 
3.9.4
Physical Examination .............................................................................55 
3.9.5
Assessment of Suicidality.......................................................................55 
3.9.6
Seizure Diary Data .................................................................................55 
3.10 
3.11
Interim Analysis .........................................................................................56 
4
DATA HANDLING ............................................................................................. 56 
4.1
Derived Endpoints and Data Handling ..........................................................56 
4.1.1
Handling of Repeated Assessments .......................................................56 
4.1.2 
4.1.3 
57
56
 55
3.8.4
46


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4.1.4 
4.1.5 
Vineland Adaptive Behavior Scales, 3rd Edition ....................................59 
4.1.6 
4.1.7
ABC-Irritability Subscale (ABC-I) ....................................................... 63 
4.1.8
Vital Sign Reference Ranges ..................................................................64 
4.2
Computation of Derived Data ........................................................................64 
4.2.1
Time Points and Duration ......................................................................64 
4.2.2
Other Data Derivations ...........................................................................64 
5
PROGRAMMING SPECIFICATIONS ...............................................................65 
5.1
Analysis Specifications ..................................................................................65 
5.2
General Specifications ...................................................................................66 
6 
REFERENCES .....................................................................................................68 
.............59
58


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LIST OF ABBREVIATIONS 
 
Abbreviation
Full Term
ABC-I 
Aberrant Behavior Checklist – Irritability Subscale 
AE 
adverse event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AS 
Angelman syndrome 
ATC 
Anatomic Therapeutic Class 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CGI-I-AS 
Clinical Global Impressions-Improvement-Angelman 
Syndrome 
CGI-S-AS 
Clinical Global Impressions-Severity-Angelman Syndrome 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
clinical study report 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
FAS 
full analysis set 
GSV 
Growth Scale Value scores from Vineland Adaptive Behavior 
Scale, 3rd Edition 
HLGT 
high level group term 
HLT 
high level term 
ICF 
informed consent form 


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ICH
International Council for Harmonisation
IDMC 
Independent Data Monitoring Committee 
ITT 
intent-to-treat set 
IWRS 
interactive web response system 
LAR 
legally acceptable representative 
LSO 
Latency of sleep onset 
MAR 
missing at random 
MedDRA
Medical Dictionary for Regulatory Activities
MI 
Multiple Imputation 
MMRM 
Mixed Model Repeated Measures 
MNAR 
missing not at random 
PBPK 
physiologically-based pharmacokinetic 
 
 
 
Peds QL™
Pediatric Quality of Life Inventory™ 
 
 
 
PK 
 
pharmacokinetic(s) 
 
 
 
PKS 
 
pharmacokinetic set 
PPS 
 
per protocol set 
PT 
 
preferred term 
Q1 
 
First Quartile 
Q3 
 
Third Quartile 
QHS 
 
each evening 
REML 
 
restricted maximum likelihood 
SAE 
 
serious adverse event(s) 


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SAP
statistical analysis plan
SD 
Standard Deviation 
SOC 
system organ class 
SS 
safety set 
TEAE 
Treatment-Emergent Adverse Event 
VABS-3 
Vineland Adaptive Behavior Scale, 3rd Edition
WHO-DD 
World Health Organization Drug Dictionary 


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pharmacokinetic (PK) and
 
 
 
1 INTRODUCTION 
Study OV101-19-001 is a Phase 3, multicenter, double-blind, placebo-controlled, 
parallel-group study. The goals of the study are to evaluate the efficacy and safety of 
once each evening (QHS) OV101 (gaboxadol) compared to placebo in pediatric 
individuals with Angelman Syndrome (AS). 
The statistical analysis plan (SAP) contains a detailed description of the data 
presentations and statistical analyses that will be included in the clinical study report 
(CSR) for Protocol OV101-19-001 version 4.0, 19 June 2020. The statistical methods 
and analyses described here are based on those presented in Section 7 of the study 
protocol. 
This study is ongoing during the Coronavirus Disease 2019 (COVID-19) pandemic, 
and as a result, there are expected to be protocol deviations related to COVID-19, 
including virtual visits (visits conducted remotely via visiting nurse, audio only, or 
audio and video) instead of clinic visits and use of local labs. Data will be collected as 
closely as possible to the Schedule of Assessments (Table 1), and analysis will be 
performed using the observed data. 
 
2 STUDY SUMMARY 
2.1 Study Objectives 
All efficacy study objectives will be assessed in the pediatric AS study population of 
subjects who are 4 to 12 years old. All 
safety study 
objectives will be assessed in the pediatric AS study population of subjects who are 2 
to 12 years old. 
Primary (Efficacy) Objective:  
x To evaluate the efficacy of OV101 versus placebo as assessed by the Clinical 
Global Impressions-Improvement-Angelman Syndrome (CGI-I-AS) score at 
Week 12. 
Key Secondary Objectives: 
 
The purpose of the key secondary objectives is to fulfil a recommendation of the 
EMA for a responder analysis. 
x To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of 
subjects who experience any meaningful improvement on study treatment 
(defined as CGI-I-AS score of 1, 2, or 3 at Week 12). 


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Tertiary (Efficacy) Objectives:
x
activity assessed by actigraphy.
To evaluate the efficacy of OV101 versus placebo on total sleep time and total
x
(caregiver reported).
To evaluate the efficacy of OV101 versus placebo based on sleep diary data
x
Sleep Habits Questionnaire (CSHQ).
To evaluate the efficacy of OV101 versus placebo based on the Children’s
x
Fatigue, and Family Impact modules).
Pharmacokinetic Objectives:
x
population 2 to 12 years old.
validated physiologically-based PK (PBPK) model for the pediatric study
approach as well as to evaluate estimated PK parameters in the context of a
following a single oral dose using sparse sampling and a population PK
concentration [Cmax] and area under the concentration-time curve [AUC]) 
To estimate systemic plasma exposure to OV101 (maximum plasma
 
 
 
x To evaluate the efficacy of OV101 vs placebo as assessed by the proportion of 
subjects who experience a response of much improved or very much 
improved (defined as CGI-I-AS score of 1 or 2 at Week 12). 
Other Secondary (Efficacy) Objectives: 
x 

x To evaluate the efficacy of OV101 versus placebo on Communication, 
Socialization, Daily Living Skills, Motor Skills, and Maladaptive Behavior 
domains assessed by the Vineland Adaptive Behavior Scales, 3rd Edition 
(VABS-3). 
x To evaluate the efficacy of OV101 versus placebo based on the Clinical 
Global Impressions-Severity-Angelman Syndrome (CGI-S-AS) Symptoms 
Overall score.  
x To evaluate the relationships of CGI-S-AS Symptoms Overall and CGI-S-AS 
domains at baseline with CGI-I-AS at Week 12. 
 
 
 
 
 
 
 
 
Safety Objectives: 
To evaluate the efficacy of OV101 versus placebo based on the Peds QL™ 
Pediatric Quality of Life Inventory™ (Cerebral Palsy, Multidimensional 
 
(Cerebral Palsy, Multidimensional
™
Pediatric Quality of Life Inventory™
™
To evaluate the efficacy of OV101 versus placebo based on the Peds QL™
p
Q
y
™


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 To evaluate the safety and tolerability of OV101 versus placebo in subjects 2 
to 12 years old, including seizure diary data and assessment of suicidality. 
 
2.2 Study Design 
A brief summary of the main study design features and assessments to be performed 
is presented here. Refer to Section 3 of the study protocol for complete details. 
This is a Phase 3, multicenter, double-blind, placebo-controlled, parallel-group study 
of OV101 treatment for 12 weeks in pediatric individuals with Angelman Syndrome. 
Subjects 4 to 12 years old will be randomized to either OV101 or placebo, while all 
subjects 2 to 3 years old will be treated with OV101. Subjects who meet all of the 
inclusion criteria, none of the exclusion criteria and who consent to participate in the 
study are eligible to be enrolled to complete a starting dose period for the first 5 study 
days and a maintenance period thereafter through Week 12. Subjects will take 
OV101 capsules orally once daily at bedtime, with dosing dependent on a subject’s 
weight and tolerance of the study drug. Subjects will visit their study site at Weeks 6 
and 12 for safety and efficacy evaluation. Efficacy evaluations are performed only in 
subjects 4 to 12 years of age. Safety evaluations are performed in all subjects 2 to 12 
years of age. An end of study (EOS) phone safety visit will occur approximately 
2 weeks after the last dose of study drug to assess safety and tolerability associated 
with discontinuation of treatment in subjects not rolling into the open label extension 
study (ELARA). Subjects eligible and willing to enroll into the ELARA study will 
have the NEPTUNE EOT visit also be their NEPTUNE EOS visit. A subject will be 
considered to have completed the study after completing the EOS visit. 
 
2.2.1 Number of Subjects 
Approximately 90 subjects 4 to 12 years old (inclusive) will be randomized into this 
study, with approximately 45 subjects in the placebo group and 45 subjects in the 
OV101 treatment group. The sample size determination is described in Section 7.3 of 
the Protocol. Approximately 5 subjects 2 to 3 years old (inclusive) will be included 
and treated with OV101. 
The study will be conducted at approximately 15 study sites and will likely involve 
variable numbers of subjects at each site. Enrollment will be on a competitive basis 
but each site will be capped at 12 subjects (unless authorized by the Sponsor). 
Activation of study sites will be centrally controlled by interactive web response 
system (IWRS). Subject randomization will be deactivated for all sites when the 
planned number of subjects is met. 
 
2.2.2 Randomization and Blinding Procedures 
Eligible subjects are required to sign the informed consent form (ICF), complete the 
screening period and assessments, and meet all inclusion/exclusion requirements. 


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Efficacy assessments will include the CGI-I-AS and CGI-S-AS scales,
VABS3, 
assessed by caregiver, 
Quality of Life Inventory™ (Peds QL™ Cerebral Palsy, Multidimensional Fatigue, and
Actigraphy, sleep diary data,
y
actigraphy measures,
sleep diary
Pediatric
and
,
CSHQ,
sleep
Family Impact modules).
 
 
Eligible subjects 4 to 12 years old (inclusive) will be assigned in a 1:1 ratio on Day 1 
to receive investigational product according to a computer-generated randomization 
schedule. Subjects will be assigned to treatment groups in sequential order as they 
qualify for the study, using a centrally located and managed IWRS. Randomization 
will be stratified by age categories: 9 to 12 years old (inclusive) and 4 to 8 years old 
(inclusive), and region: US and outside US, with at least 24 subjects per age category. 
Upon randomization, each subject will receive a subject randomization number and a 
drug kit assignment.  
This is a double-blind, placebo-controlled study. The sponsor, investigators, study 
coordinators, pharmacists, and study subjects will be blinded to the study medication. 
To maintain blinding of the individual treatment assignment, the results of 
pharmacokinetic testing will not be made available to any study personnel or subjects. 
If knowledge of the treatment is needed to manage the subject’s condition, the 
investigator will contact the IWRS to obtain the treatment assignment. If unblinding 
occurs for any reason, the time and reason for breaking the blind will be recorded on 
the electronic case report form (eCRF) and the sponsor must be notified within 24 
hours. 
A designated statistician who is not involved with the study operation will hold the 
treatment codes. The Independent Data Monitoring Committee (IDMC) will review 
blinded data, but will also have the ability to review unblinded data as needed to 
evaluate benefit risk during the study. For example, the unblinded treatment 
information can be provided to the IDMC to facilitate the evaluation of any clinically 
important increase in the rate of a serious suspected adverse reaction or to the 
designated safety contact when the treatment information is required to determine if 
an expedited safety report must be submitted to regulatory agencies. The IDMC and 
relevant unblinded personnel should prevent any risk of unblinding of data to the 
sponsor, investigators, study coordinators, pharmacists, and study subjects. 
Eligible subjects 2 to 3 years old (inclusive) will be treated with OV101, and their 
treatment is not blinded. 
 
2.2.3 Efficacy Assessments 
 
 
CGI-S-AS will be collected at Screening, Baseline, Weeks 6 and 12. CGI-I-AS will 
be assessed at Weeks 6 and 12. 
and CSHQ will be 
obtained at Baseline, Week 6 and Week 12. The VABS-3 and Peds QL™ instruments 
will be administered at Baseline and Week 12. 
g
w
™i
nd CSHQ w
Peds QL™
Q
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2.2.3.1 Clinical Global Impressions Scales 
The CGI-S-AS scale with AS-specific anchors will be used by the investigator to 
assess the severity of symptoms, and the CGI-I-AS scale will be used by investigators 
to assess improvement from baseline. The CGI-S-AS has been adapted to capture 
specific characteristics commonly present in the AS population. The CGI-I-AS 
captures clinical impression that reflects the rater’s estimate of change from the 
initiation (Baseline) of treatment. Both the CGI-S-AS and the CGI-I-AS assessments 
will be conducted by a clinician rater with experience in AS and trained in CGI-S-AS 
and CGI-I-AS rating by the Sponsor. The rater should be the same rater throughout 
the study for a given subject (on the eCRF, the investigator will be identified as either 
the same or different since the last time the subject was seen). As an exception, a 
clinician sub-investigator, trained in CGI-S-AS and CGI-I-AS rating by the Sponsor, 
may be used. The Baseline CGI-S-AS will be accompanied by detailed Investigator 
Notes. Each CGI-I-AS rating at Week 6 and Week 12 will also be accompanied by 
detailed Investigator Notes. In order to reduce recall bias, within 24 hours prior to the 
Week 6 CGI-I-AS rating, the rater will review the CGI-S-AS rating and Investigator 
Notes from the baseline visit and within 24 hours prior to the Week 12 CGI-I-AS 
rating, the rater will review the CGI-S-AS rating and Investigator Notes from the 
baseline visit and CGI-I-AS rating and Investigator Notes from Week 6. If the CGI-I- 
AS assessment is missing at Week 6 or 12, the reason for its absence will be collected 
on the eCRF. 
 
2.2.4 Safety Assessments 
Adverse event (AE) occurrences will be recorded throughout the study. Adverse 
events will be assessed beginning on the date of signed informed consent and up to 
14 days after the last dose of study drug (unless a subject decides to participate in the 
ELARA open-label extension study) and must be followed until resolution or for 
14 days after the subject’s last study drug dose, whichever comes first. If the 
investigator becomes aware of an SAE within 30 days after the subject’s last 
dose of study drug or within 30 days after the last study visit or more than 30 days 
after the last dose of study drug if considered by the investigator to be related to study 
drug, the SAE must be reported. 
Seizures in this subject population will be detected and assessed using the seizure 
diary. Diaries will be collected at the study site during the study and will be analyzed 
by the sponsor along with the reportable serious AEs (SAEs) in evaluating risks and 
benefits. The sponsor will report the SAE events of seizure that meet the criteria for 
reporting seizures as an AE (protocol section 6.4.1.1) in an aggregated, unblinded 
report at the end of the study. 
Self-harm will be determined using the Aberrant Behavior Checklist – Irritability 
Subscale (ABC-I), which is one of the five subscales of the Aberrant Behavior 


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determination of OV101 concentrations.
minutes, 90 minutes ± 15 minutes and 4 hours ± 30 minutes after dosing for
dose of study drug at the study site. Blood will be sampled at 45 minutes ± 15
Pharmacokinetic measures will be collected on Day 1, after subjects take their first
 
 
Checklist – Community (ABC-C). Additional safety assessments include clinical 
laboratory analyses, vital sign measurements, and physical examinations. 
2.2.5 
 
Pharmakokinetic Assessments


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Visit Name 
 
Screening 
 
Baseline 
Phone/ 
Titration 
 
Week 6 
EOT/ 
Week 12 
 
EOS  
 Phone/  
Week 14  
Window  D –28 to   
+1 Day 
±3 Days 
+3 Days 
±2 Days 
 
D –1  
Day  
Day 1 
Days 6  
Day 43 
Day 85 
Day 99 
and 11
Event  
 
 
 
 
 
 
Informed consent and  
X 
 
 
 
 
 
assenta  
Demographics  
X 
 
 
 
 
 
Inclusion/exclusion criteria
X 
Xb 
Medical history 
X 
 
Xb,c  
 
 
 
 
Clinical assessmentd for  
X 
 
Xb,c  
X 
X 
X 
X 
AS  
 
Molecular AS teste  
X 
 
 
 
 
 
Dose titration  
 
 
Xf 
 
 
 
Physical examination
X 
Xb,c
X 
X 
Vital signs  
X 
Xb 
X 
X 
 
Clinical laboratory tests  
X 
 
Xb,c  
 
X 
X 
 
Adverse events
X 
Xb 
X 
X 
X 
X 
Concomitant medications  
X 
 
Xb,c  
X 
X 
X 
X 
Assessment of suicidality:  
X 
X 
X 
X 
X 
X 
ABC-Im  
Seizure diary issued 
X 
X 
X 
 
 
Seizure diary collected and
 
X 
X 
X 
 
reviewed, SIF/DRF forms  
completed/submitted l  
Sleep diary issued  
X 
X 
X 
 
 
Sleep diary collectedg  
 
X 
X 
X 
 
Actigraph issuedh  
X 
 
 
 
 
 
Actigraph collected  
 
 
 
 
X 
 
Dispense study drug 
 
X 
X 
 
 
Collect unused study drug   
 
 
X 
X 
 
Review medication diary  
 
 
 
X 
X 
 
PK samplingi  
 
X 
Table 1. Schedule of Activities


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X
X
X
X
X
Visit Name
Screening
Event 
CGI-S-AS 
CGI-I-ASj 
VABS-3k 
Children’s Sleep Habits 
Questionnaire 
Pediatric Quality of Life 
Inventory
X
Xb
X
X
X
X
X
Window
D –28 to
D –1 
+1 Day
±3 Days
+3 Days
±2 Days
Day
Day 1
Days 6
and 11
Day 43
Day 85
Day 99
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ABC-I, Aberrant Behavior Checklist-Irritability subscale; AS, Angelman syndrome; 
CGI-I-AS, Clinical Global Impressions-Improvement Angelman syndrome; CGI-S-AS, Clinical 
Global Impression-Severity Angelman syndrome; D, day(s); EOS, end of study; EOT, end of 
treatment; PK, pharmacokinetic; VABS-3, Vineland Adaptive Behavior Scale, 3rd Edition. 
Notes: Phone visits may take the form of a video phone call. For subjects completing the study per 
protocol, the Week 12 visit will be the EOT, and the EOS phone visit will occur at Week 14. For 
subjects discontinuing treatment before Week 12, the EOT visit will occur within 2 weeks after 
discontinuing treatment, and the EOS phone visit will occur 2 weeks after the EOT visit. 
a 
There will be separate informed consent and assent forms for the caregivers and subjects, 
respectively. 
b 
Baseline visit assessment that must be completed prior to administration of study drug on Day 1. 
c 
If the screening and baseline visits can be completed within 14 days, the following assessments do 
not need to be repeated at the baseline visit: medical history, clinical assessment, physical 
examination, clinical laboratory tests, and determination of concomitant medications. Female 
subjects who have experienced menarche will undergo serum beta-human chorionic 
gonadotrophin pregnancy testing.  
d 
Signs and symptoms of AS. 
e 
Only required if no written evidence for molecular diagnosis is available in the subject records. 
f 
Down-titration may be initiated on Day 11 by 1 capsule based on the Investigator’s assessments of 
tolerability and adverse events, or medical necessity. If down-titration is initiated, then the 
investigator should reassess tolerability with the modified dose regimen within 3 days of the 
dosing change. No further changes in dose regimen should be made after Day 15. 
g 
Caregivers will complete sleep diaries on behalf of subjects during the days the subject is wearing 
the actigraph. Study site staff will call LAR/caregivers to remind them when to start recording data 
in the sleep diary. 
h 
An actigraph must be issued to each subject at the screening visit, so that actigraphy data can be 
collected for 7 days (3 attempts within the 28-day screening period are allowed) before the 
baseline visit. 
EOS
Phone/ 
Week 14
Week 12
EOT/
Week 6
Titration
Phone/
Baseline


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j
baseline CGI-S-AS score and investigator notes. Within 24 hours prior to the subject’s visit at 
Week 12, the investigator must review the subject’s baseline CGI-S-AS score and investigator 
CGI-S-AS and CGI-I-AS rating by the Sponsor, must be used throughout the study to assess a 
given subject. It is recommended that the same rater be used at a given site. As an exception, a
k
l
A Seizure Identification Form and Diagnostic Review Form (SIF/DRF) will be completed by site
Within 24 hours prior to the subject’s visit at Week 6, the investigator must review the subject’s 
blood sampling after the initial dose.
starting with the evening of Day 2 Study site staff will record the time of dosing and the times of
site. Subjects will take all subsequent doses approximately 30 minutes before anticipated bedtime, 
minutes ± 15 minutes, 90 minutes ± 15 minutes, and 4 hours ± 30 minutes after dosing at the study 
notes and the Week 6 CGI-I-AS score and investigator notes. The same clinician rater, trained in 
another Sponsor-trained qualified rater in VABS-3 may be used 
caregiver. For each study site, the same rater is to be used throughout the study. As an exception,
The VABS-3 will be assessed by a trained qualified rater based on an interview of the subject’s 
clinician sub-investigator, trained in CGI-S-AS and CGI-I-AS rating by the Sponsor, may be used. 
m
The entire Aberrant Behavior Checklist – Community (ABC-C) will be administered. Only ABC-I 
enrolled/completed the study if feasible. 
seizures are classified accurately. SIF and DRF forms will be collected for patients who have 
Study Consortium (TESC) for review and approval. The SIF/DRF will be used to ensure that the
personnel for every eligible subject. This information will be faxed or emailed to The Epilepsy 
 
 
i 
 
 
 
 
 
 
will be used to evaluate the potential for self-harm 
At baseline, sampling of blood for determination of concentrations of OV101 will occur 45 
will be used to evaluate the potential for self-harm 
At baseline, sampling of blood for determination of concentrations of OV101 will occur 45


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3 STATISTICAL METHODS 
3.1 General Methods 
3.1.1 Computing Environment 
All statistical analyses will be performed using SAS® Version 9.4 or higher. 
 
3.1.2 Reporting of Numerical Values 
All clinical study data will be presented in subject data listings. Data summaries will 
be presented for all endpoints and will include descriptive statistics (number of 
subjects [n], mean, standard deviation [SD], first quartile [Q1], median, third quartile 
[Q3], minimum and maximum) by treatment group for continuous variables. 
Frequencies and percentages will be presented by treatment group for categorical and 
ordinal variables. If there are missing values, the number missing will be presented, 
but without a percentage. All percentages will be based on the number of subjects 
with non-missing values. Confidence intervals will be provided where appropriate. 
Means, quartiles, and confidence intervals will be reported to one decimal place more 
than the data reported on the eCRF or by the laboratory/vendor. Standard deviations 
will be reported to two decimal places more than the data reported. Minimum and 
maximum will be reported to the same number of decimal places displayed on the 
eCRF or by the laboratory/vendor. P-values will be reported to 4 decimal places. 
 
3.1.3 Statistical Testing and Significance Level 
The primary efficacy analysis will be performed on the full analysis set (FAS) and the 
per protocol set (PPS), which are defined in Section 3.2. However, the PPS analysis 
will only be considered a sensitivity analysis. 
Inferential treatment comparison of the primary efficacy endpoint, CGI-I-AS at Week 
12, will be conducted at the 0.05 level of significance using a two-tailed test. If the 
null hypothesis of no treatment difference for the primary endpoint is rejected, the 
alpha (0.05) will be passed to the significance testing for the keysecondary efficacy 
endpoints (added to fulfill an EMA recommendation for responder analysis), CGI-I- 
AS response (at least minimally improved) at Week 12 and CGI-I-AS response (at 
least much improved) at Week 12, which will be tested using the corresponding 2- 
sided tests at 0.05 level of significance in a fixed sequence. If and only if the null 
hypothesis of no treatment difference based on CGI-I-AS response (at least minimally 
improved) is rejected at 0.05 level of significance, testing will continue and the null 


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12 latency to sleep onset and sleep efficiency)
actigraphy
study drug, then ABC-C at screening will be used as baseline.
QL™). If the ABC-C on Day 1 is administered in the clinic after the first dose of
referring back to the time period before the baseline clinic visit (e.g. CSHQ, Peds
with the exception of assessments by the caregiver
 
 
hypothesis of no treatment difference based on CGI-I-AS response (at least much 
improved) will be tested at 0.05 level of significance. 
 
No formal statistical testing of other secondary endpoints will be performed. The p- 
values presented for other secondary and tertiary endpoints will not be adjusted for 
multiplicity and will be considered descriptive in nature.  
 
3.1.4 Baseline Value and Change from Baseline 
Baseline value is defined as the latest non-missing value obtained prior to 
administration of first dose, 
 
 
Change from baseline 
will be calculated by subtracting the baseline value from the post-dose assessment for 
each subject (i.e., post-dose – baseline). 
 
3.1.5 Study Day 
Day 1 will be defined as the day of first dose of investigational product during the 
Treatment Period. Study day for events prior to randomization and first dose will be 
determined as Study Day = (Event Date – First Dose Date). Study day for events on 
or after first dose will be determined as Study Day = (Event Date – First Dose Date) + 
1. 
 
3.1.6 Handling of Missing/Incomplete Values 
3.1.6.1
Missing or Incomplete Efficacy Endpoints 
To the extent possible, attempts will be made to minimize the amount of missing data 
through measures planned in the study conduct. Due to the scale of the study and the 
anticipated small number of missing data for the primary efficacy endpoint (Week 12 
CGI-I-AS), no simple imputation for the missing data will be performed. However, if 
missing data are more than 3% for the primary efficacy endpoint, a sensitivity 
analysis will be performed. The missing data will be handled using a multiple 
imputation approach (including a tipping point analysis), as a part of the sensitivity 
analysis, as described in Section 3.8.6 of this SAP. 
For each of the 
endpoints within the other secondary endpoint set 
if more than 5% but less than 20% of 
the subjects have missing values, sensitivity analyses will be performed where 
missing data will be handled using a multiple imputation approach, as described in 
Section 3.8.6 of this SAP. 
(Week


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except for actigraphy, sleep diary,
 
 
For any other secondary or tertiary efficacy endpoints, the missing data will not be 
imputed and only the observed data will be used for analyses. 
 
3.1.6.2
Missing and Incomplete Dates 
Partial medication dates will be imputed with maximum conservatism when 
determining if a medication is concomitant. The rules used for imputation of dates in 
concomitant medication analyses are detailed in section 3.5 of this SAP. 
AE start dates will be imputed but AE stop dates will not be imputed. Rules for 
handling incomplete or missing AE start dates are detailed in section 3.8.1 of this 
SAP. 
No other baseline or safety data points will be imputed. 
 
3.1.7 Methods of Pooling Data 
Because of the large number of centers relative to the number of subjects, an analysis 
adjusted by study center is not planned. Similarly, it is not expected to have a 
sufficient number of subjects in each country involved in the study to adjust for 
country. However, descriptive analysis will be performed by country for the primary 
efficacy endpoint. 
 
3.1.8 Analysis Visit Windows 
Visit windows for study conduct are specified in Table 1: Schedule of Activities. 
Unless otherwise specified, the following analysis visit rules will be implemented for 
all endpoints 
and seizure diary (see sections 3.8.3, 
3.8.4, and 3.9.6 for analysis visit window computations). For all unscheduled visits 
and end of treatment (EOT) visits from subjects discontinuing treatment early (before 
Week 12), assessments will be mapped according to the analysis visit windows in 
Table 2 for primary summarization and analysis. If the visit does not fall within any 
of the analysis visit windows, then the visit will be considered missing at the 
specified time point for analysis purposes. 
Table 2: Nominal (Targeted) Time Points and Analysis Visit Windows 
 
 
Assessment 
Nominal (Targeted) Time 
Point 
Analysis Visit Window 
(Interval in Study Days) 
Baseline Assessments
Study Day 1
≤Day 1
Phone/Titration (Day 6)
Study Day 6
>Day 1 - ≤Day 8
Phone/Titration (Day 11)
Study Day 11
≥Day 9 - ≤Day 21
Week 6 (Study Day 43)
Study Day 43
≥Day 22 - ≤Day 64
Week 12 (Study Day 85)
Study Day 85
≥Day 65 - ≤Day 92
Week 14 (Study Day 99)
Study Day 99
≥Day 93


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After mapping the data from unscheduled and end of treatment (EOT) visits from 
subjects discontinuing treatment early to the nominal time point, the following rules 
will apply if multiple records are available within a single analysis visit window 
unless otherwise specified for a particular analysis: 
 If a record exists for the nominal time point, that record will be selected for 
analysis. 
 If a record for the nominal time point does not exist and multiple records are 
available within a single analysis visit window, 
o The record closest to the planned assessment day will be selected for 
analysis 
o If 2 records are equidistant from the target day, then the earliest record 
will be selected (does not apply to the Week 12 or 14 visits). 
 If a subject has no record in an analysis window, the subject will be 
considered missing at that time point. 
For the primary and key secondary objectives, a supportive analysis will be 
conducted in which CGI-I-AS assessments from unscheduled visits and end of 
treatment (EOT) visits from subjects discontinuing treatment early (before Week 12) 
will be mapped according to the analysis visit windows in Table 3. 
Table 3: Nominal (Targeted) Time Points and Alternative Analysis Visit 
Windows 
 
 
Assessment 
Nominal (Targeted) Time 
Point 
Analysis Visit Window 
(Interval in Study Days) 
Baseline Assessments
Study Day 1
≤Day 1
Week 6 (Study Day 43)
Study Day 43
>Day 1 - ≤Day 43
Week 12 (Study Day 85)
Study Day 85
>Day 43
After mapping the data to the nominal time point, the following rules will apply if 
multiple records are available within a single analysis visit window unless otherwise 
specified for a particular analysis: 
 If a record exists for the nominal time point, that record will be selected for 
analysis. 
 If a record for the nominal time point does not exist and multiple records are 
available within a single analysis visit window, 
o The record closest to the planned assessment day will be selected for 
analysis 
o If 2 records are equidistant from the target day, then the earliest record 
will be selected (does not apply to the Week 12 visit). 
 If a subject has no record in an analysis window, the subject will be 
considered missing at that time point. 


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In addition, for the primary and key secondary objectives, an additional supportive 
analysis will be conducted in which CGI-I-AS assessments will be analyzed 
according to the nominal visit time point (i.e. only records identified as baseline and 
records from the Day 43/Week 6 and Day 85/EOT/Week 12 visits will be included). 
 
3.2 Analysis Populations and Subgroups 
3.2.1 Definition of Analysis Populations 
The following analysis sets, with the exception of the Intent-to-treat and Safety Set, 
will only include subjects 4 to 12 years old (inclusive) at screening. The baseline and 
safety analyses for subjects 2 to 3 years old (inclusive) at screening will be conducted 
separately. 
Intent-to-Treat Analysis Set 
The intent-to-treat set (ITT) will consist of all subjects who are randomized (subjects 
aged 4 to 12 years old (inclusive) or enrolled (subjects aged 2 to 3 years old 
(inclusive) and meet all inclusion and exclusion criteria), whether or not study drug is 
received. Subjects aged 4 to 12 years old (inclusive) will be analyzed according to 
their randomized treatment. 
Full Analysis Set 
The full analysis set (FAS) will include all subjects aged 4 to 12 years old (inclusive) 
who are randomized, receive at least 1 dose of study drug, and have at least 1 post- 
baseline assessment of the primary efficacy endpoint. The FAS will be used for 
efficacy analyses based on the randomized treatment for each subject. 
Per Protocol Set 
The per protocol set (PPS) is a subset of the FAS that includes subjects who complete 
the Week 12 CGI-I-AS assessment (with appropriate visit mapping as shown in Table 
2) and have no major protocol deviations that are deemed to impact efficacy. These 
violations include but are not limited to violations of inclusion/exclusion criteria 
deemed to impact efficacy, inadequate study drug compliance over the dosing period 
as determined from the dosing information in the eCRF, usage of prohibited 
concomitant medications, and incorrect randomization. Additionally, other relevant 
protocol deviations, such as early termination or interruption of treatment, may be 
identified for review. 
Prior to database lock and unblinding, there will be a meeting to review all protocol 
deviations to determine PPS exclusions. The threshold for percent compliance that 
would be considered inadequate and would result in exclusion from the PPS will also 
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LSO, defined as time from beginning of rest period to start of sleep
Pharmacokinetic Set
of study drug and have at least one valid PK measurement.
The pharmacokinetic set (PKS) will consist of all subjects who receive at least 1 dose 
o
 
 
information. The PPS will be used for efficacy analyses based on the randomized 
treatment for each subject. 
Safety Set 
The safety set (SS) will consist of all subjects in the ITT who receive at least 1 dose 
of study drug and will be used for safety analyses. The safety analyses will be based 
on the treatment that was actually administered to each subject and will be conducted 
separately for subjects 2 to 3 years old (inclusive) and subjects 4 to 12 years old  
(inclusive).  
 
 
 
3.2.2 Definition of Subgroups 
Subgroups will be defined by age group (randomization stratification variable: age 4 
to 8 years versus age 9 to 12 years) and by region (randomization stratification 
variable: US versus outside US). 
 
3.3 Analysis Endpoints 
3.3.1 Primary Efficacy Endpoint 
x The CGI-I-AS score at Week 12 
3.3.2 Key Secondary Efficacy Endpoint 
x CGI-I-AS response (at least minimally improved) defined as CGI-I-AS score 
of 1, 2, or 3 at Week 12 
x CGI-I-AS response (at least much improved) defined as CGI-I-AS score of 1 
or 2 at Week 12 
The key secondary endpoints will be utilized to fulfill a recommendation of EMA for 
a responder analysis. 
 
3.3.3 Other Secondary Efficacy Endpoints 
x


o
onset
duration of the rest period
Sleep efficiency, defined as the percentage of total sleep time out of
Actigraphy assessment scores, change from Baseline to Week 12
LSO, defined as time from beginning of rest period to start of sleep
onset


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3.3.4 Tertiary Efficacy Endpoints
o
Total sleep time at night defined as duration of sleep time in the sleep 
interval 
x
Sleep diary assessment scores, change from Baseline to Week 12
o
Latency of sleep onset defined from subject in bed to time of subject 
sleep onset 
o
Sleep efficiency defined as the percentage of total sleep time out of the 
duration of time in bed 
o
Total sleep time at night defined from subject time of sleep onset to 
time of awakening 
x
o Number of night awakenings 
o Duration of night awakenings 
o Number of disruptive behaviors while in bed 
o Daytime sleep defined as duration of napping 
CSHQ assessment scores, change from Baseline to Week 12
 
 
x VABS-3 assessment scores, change from Baseline to Week 12 
o Total Score (Adaptive Behavior Composite Score)  
o Communications domain and its subdomains 
o Socialization domain and its subdomains 
o Daily Living Skills domain and its subdomains 
o Motor Skills domain and its subdomains 
o Maladaptive Behavior subdomains 
x CGI-S-AS scores, change from Baseline to Week 12 
o The CGI-S-AS symptoms overall score 
o The CGI-S-AS domain scores 
x 






o
o 
o
Total score
Sleep-Onset Delay Subscale score
Bedtime Resistance Subscale score
Actigraphy assessment scores, change from Baseline to Week 12
3.3.4 Tertiary Efficacy Endpoints
Sleep-Onset Delay Subscale score
o
o
o
Bedtime Resistance Subscale score
Total score
CSHQ assessment scores, change from Baseline to Week 12
o
HQ
Daytime sleep defined as duration of napping
assessment scores change from Baseline to We
o
o
Number of disruptive behaviors while in bed 
Daytime sleep defined as duration of napping
o
o
Duration of night awakenings
Number of disruptive behavior
o
o
Number of night awakenings
D
ti
f i ht
k
i
x
Total sleep time at night defined from subject time of sleep onset to
time of awakening
N
b
f i ht
o
Sleep efficiency defined as the percentage of total sleep time out of the
duration of time in bed 
T t l l
ti
t i h
o
Latency of sleep onset defined from subject in bed to time of subject
sleep onset 
Sl
ffi i
o
Sleep diary assessment scores, change from Baseline to Week 12
L t
f l
t d fi
d f
bj
t i b d t ti
x
Total sleep time at night defined as duration of sleep time in the sleep
interval 
o
Actigraphy assessment scores, change from Baseline to Week 12


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x
from Baseline to Week 12
Pediatric Quality of Life Inventory™ (Peds QL™) assessment scores, change
3.3.5 Exploratory Efficacy Endpoints
o
Total daytime sleep (changed to an exploratory endpoint because 
optimal sleep algorithm scoring settings need to be determined, based 
on the highest value of the intraclass correlation coefficient of 
actigraphy daytime sleep with sleep diary daytime sleep) 
x
Behavior, Hyperactivity/Non-compliance, and Inappropriate Speech 
ABC-C subscale scores for Lethargy/Social Withdrawal, Stereotypic
o
Daily activity level


o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 



3.3.6 Safety Endpoints 
x Incidence of adverse events 
x Change in clinical laboratory parameters from Baseline to each post-baseline 
assessment 
x Shift in clinical laboratory parameters from Baseline to each post-baseline 
assessment 
x Change and shift in vital sign measurements from Baseline to each post- 
baseline assessment 
Family Impact module scores by dimension, total scores including the
Score
Parent HRQL Summary Score, the Family Functioning Summary
Actigraphy assessment scores, change from Baseline to Week 12
Multidimensional Fatigue module by dimension and total score
Cerebral Palsy module by dimension score
o 
o
o
Morning Waking/Daytime Sleepiness Subscale score 
Sleep-Disordered Breathing Subscale score
Parasomnias Subscale score
Behavior Occurring Around Night Wakings Subscale score
Anxiety Around Sleep Subscale score
o 
o 
o 
o
o
Sleep Duration Subscale score
Family Impact module scores by dimension, total scores including the
Parent HRQL Summary Score, the Family Functioning Summary
x
x


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3.3.7 Pharmacokinetic Endpoints
x
min, 90 minutes ± 15 min, 4 hours ± 30 min)
OV101 plasma concentration at each PK sampling window (45 minutes ± 15
x
validated PBPK model.
exposure estimates (Cmax and AUC) will also be evaluated in the context of a
OV101 PK parameters derived from population PK modelling: Population PK
 
 
x Change in suicidality assessment (ABC-I) from Baseline to each post-baseline 
assessment. The ABC-I will serve as a surrogate measure for suicidality 
x Percent change in seizure frequency (collected in seizure diary) per 28 days 
from Baseline to each post-baseline time point 
 
 
 
 
3.4 
Subject Disposition and Evaluability 
3.4.1 Subject Disposition 
The number of subjects screened and who failed screening will be displayed. The 
number and percentage of subjects who are randomized, dosed, withdrawn from the 
study (including reasons for withdrawal), complete the study, the number of subjects 
with a Week 6 remote visit performed, and the number of subjects with a remote 
Week 12 visit performed will be displayed for subjects 4-12 years old (inclusive) by 
treatment group and overall for all subjects who signed informed consent. The 
number and percentage of subjects in the ITT, SS, FAS, PPS, 
displayed by treatment group and overall. 
will also be 
The number of subjects who screened, dosed, completed the study, withdrew from the 
study, and the number and percentage of subjects in the ITT and SS will be 
summarized separately for subjects 2 to 3 years old (inclusive). The number of 
subjects with a Week 6 remote visit performed, and the number of subjects with a 
remote Week 12 visit performed will also be included. 
In addition, for subjects 4-12 years old (inclusive) and separately subjects aged 2 to 3 
years old (inclusive), a summary table of subjects with at least one visit affected by 
COVID-19 will be presented. A separate subject listing of subject visits and 
assessments affected by COVID 19 will be provided. 
A by-subject listing of study completion information will be presented. A by-subject 
listing of subjects who are screen failures, and the reason for screen failure, will also 
be presented. 
and PKS
x


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3.4.2 Protocol Deviations 
The number and percent of subjects with at least one major protocol deviation and the 
number and percent of subjects with at least one major deviation of each deviation 
type will be presented by treatment group and overall for the FAS. All relevant 
protocol deviations will be shown in a subject listing by treatment group. Subjects 
with major deviations identified as exclusions from the per-protocol analysis set will 
be indicated in a listing. In addition, deviations related to COVID-19 will be 
identified in a separate listing. 
A separate listing of reasons for exclusion from the Per Protocol Set for subjects ages 
4-12 years old (inclusive) will also be provided. 
 
3.5 Demographics and Baseline Characteristics 
3.5.1 Demographics 
All demographic and baseline characteristics data will be summarized descriptively 
for subjects 4-12 years old (inclusive) by treatment group and overall for the SS, FAS, 
and PPS. A separate summary will be provided for subjects 2-3 years old (inclusive) 
in the SS. 
Descriptive statistics will be displayed for age at screening, age at baseline, height, 
weight at baseline, and body mass index (BMI). Age at screening (collected as age 
at time of informed consent) is recorded at the time of randomization (or enrollment 
for subjects aged 2 to 3 years). In addition, if the age of the subject changed between 
signing of informed consent and the randomization (enrollment) visit, this 
information is also recorded. For such cases in which the age is reported to have 
changed, one year is added to age at screening to determine age at baseline. For all 
other subjects, age at baseline is set to the age at screening. Height, weight and BMI 
will be summarized with the data collected at the baseline visit. 
Frequencies and percentages will be tabulated for age group (randomization 
stratification variable: age 4 to 8 years versus age 9 to 12 years) [for subjects 4-12 
years old (inclusive) only], region, gender, race, ethnicity, study center, country and 
history of seizures. History of seizures will be categorized as follows: 
 Yes, seizure within last two years (defined as seizures within the same year or 
the year before informed consent) 
 Yes, but no seizure within the last two years 
 Yes, but unknown status in last two years 
 No 


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 Unknown. 
All demographics and baseline characteristics will be presented by subject in a data 
listing. 
 
3.5.2 Medical History 
All medical history conditions will be coded using the Medical Dictionary of 
Regulatory Activities (MedDRA, Version 22) and will be classified by MedDRA 
system organ class (SOC) and preferred term (PT). Medical history will be tabulated 
separately for subjects 4-12 years old (inclusive) and subjects 2-3 years old 
(inclusive) by SOC and PT for each treatment group and overall for the SS. All 
medical and surgical history conditions will be included in subject data listings. 
 
3.5.3 Seizure History 
Seizure history will be included in a subject data listing for subjects in the SS, sorted 
by age group at screening (subjects 4-12 years old (inclusive) and subjects aged 2 to 3 
years old (inclusive)). 
 
3.6 Prior and Concomitant Medications 
Prior medications are defined as medications that started before first study drug 
administration and either stopped before or continued after first study drug 
administration. Concomitant medications are defined as medications that are being 
taken while on study drug. Medications that are ongoing on the date of the first 
administration of study drug will be classified as both prior and concomitant. Any 
medication that cannot be confirmed as stopping before the start of study drug will be 
classified as both a prior and a concomitant medication. 
Partial medication dates will be imputed with maximum conservatism when 
determining if a medication is concomitant. If the onset date is missing or partial, the 
date will be compared as far as possible with the date of first dose of study 
medication. If no month is present and it is in the same year as the date of first 
treatment, or the year and month are the same as the first treatment date, the onset 
date will be imputed as the date of first treatment. Otherwise it will be imputed as 01 
January in the available year, or the first day of the month and year available. End 
dates will be imputed as 31 December in the available year, or the last day of the 
available month and year collected. The imputed start date must be less than or equal 
to the imputed stop date. 
All medications will be coded with the WHO Drug Dictionary (WHO-DD B3 format, 
March 2019). Prior and concomitant medications will be summarized separately and 
the number and percentage of subjects in each treatment group who took at least one 


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prior (concomitant) medication as well as the number and percentage of subjects who 
took each type of medication will be summarized separately for subjects 4-12 years 
old (inclusive) and subjects 2-3 years old (inclusive) by Anatomic Therapeutic Class 
(ATC) Level 2, ATC Level 4, and Preferred Term (PT) for the SS. If a subject has 
more than one occurrence of the same PT, then the PT will be counted only once for 
that subject. Similarly, if a subject has more than one PT within ATC Level 4 or 
ATC Level 4 within ATC Level 2, then the subject will be counted only once in that 
ATC Level 4 or ATC Level 2. 
 
3.6.1 Non-Benzodiazepine Concomitant Medication 
A separate summary of non-benzodiazepine concomitant medications indicated for 
seizure therapy will also be presented. Non-benzodiazepine medications will be 
classified based on WHO-DD ATC Level 2, ATC Level 4 and PT, as appropriate, 
prior to unblinding at database lock. Full details of the classification will be provided 
in the analysis data specifications. The number and percentage of subjects in each 
treatment group who took at least one non-benzodiazepine medication for seizure 
therapy, only one non-benzodiazepine medication for seizure therapy, two non- 
benzodiazepine medications for seizure therapy, three or more non-benzodiazepine 
medications for seizure therapy, as well as the number and percentage of subjects who 
took each type of non-benzodiazepine medication will be summarized separately for 
subjects 4-12 years old (inclusive) and subjects 2-3 years old (inclusive) by Anatomic 
Therapeutic Class (ATC) Level 2, ATC Level 4, and Preferred Term (PT) for the SS. 
A similar summary will be presented for non-benzodiazepines indicated for sleep. 
Medications with an indication for seizure therapy and with an indication for sleep 
will also be classified prior to unblinding at database lock and detailed in the analysis 
data specifications. 
 
3.6.2 Benzodiazepine Concomitant Medication 
A summary of benzodiazepine concomitant medications by dose frequency (As 
Needed, Immediately (STAT), Regularly, Unknown, Other) will also be presented. 
Benzodiazepine medications will be classified based on WHO-DD ATC Level 2, ATC 
Level 4 and PT, as appropriate, prior to unblinding at database lock. Full details of 
the classification will be provided in the analysis data specifications. For each dose 
frequency, the number and percentage of subjects in each treatment group who took at 
least one benzodiazepine medication, only one benzodiazepine medication, two 
benzodiazepine medications, three or more benzodiazepine medications, as well as 
the number and percentage of subjects who took each type of benzodiazepine 
medication will be summarized separately for subjects 4-12 years old (inclusive) and 
subjects 2-3 years old (inclusive) by ATC Level 2, ATC Level 4, and PT for the SS. A 
similar summary will be presented for benzodiazepines indicated for seizure therapy 


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by dose frequency. In addition, a summary of benzodiazepines indicated for non- 
seizure therapy by dose frequency will also be presented. 
 
3.6.3 Most Common Concomitant Medication 
A table of the most common concomitant medications for subjects aged 4 to 12 years 
old (inclusive) and separately for subjects 2-3 years old (inclusive) will be presented. 
The most common concomitant medications are those with an incidence ≥10% 
overall. The number and percentage of subjects in each treatment group who took at 
least one of the most common concomitant medications as well as the number and 
percentage of subjects who took each type of medication will be summarized by ATC 
Level 2 for the SS. 
All prior and concomitant medication data will be listed for subjects in the ITT, 
including the WHO Drug ATC 2 and ATC 4 class, PT term, the investigators verbatim 
description and the classification as prior, concomitant or both. Medications will be 
sorted by medication start date within subject. Rescue medications and anti-epileptic 
medications will be flagged. Separate listings will be provided for benzodiazepine 
and non-benzodiazepine medications. 
Concomitant procedures will be presented in subject listings for subjects in the ITT. 
 
3.7 Treatment Exposure and Compliance 
3.7.1 Exposure to Study Treatment 
Treatment duration or days on treatment (defined as Last dose date – First dose date + 
1) will be described for the SS, separately for subjects aged 2 to 3 years old 
(inclusive) and 4 to 12 years old (inclusive), and for the FAS using summary 
statistics. Additionally, study drug administration method to be used throughout the 
study (capsule or powder) as recorded at baseline and the number of subjects with at 
least one missed dose will also be presented. A missed dose is defined as at least one 
day when study medication was not administered as reported on the medication diary, 
with a missing diary day considered as dose not administered. Treatment duration 
frequencies will be summarized for the intervals 1 to ≤5 days, 6 to ≤11, 12 to ≤42 
days, 43 to ≤70, 71 to ≤84 days, 85 days or more by treatment group and overall. 
Furthermore, treatment duration frequencies will also be summarized for the same 
intervals described above by weight band at screening (9 to 16.99 kg, 17 to 24.99 kg, 
25 to 34.99 kg, 35 to 44.99 kg, and 45 to 64.99 kg). 
 
3.7.2 Compliance to Protocol Intended Dose 
Treatment compliance will be summarized for the SS and FAS for subjects aged 4 to 
12 years old (inclusive) and for the SS for subjects 2-3 years old (inclusive), by 


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treatment group over the entire treatment period. Study drug is dispensed at Baseline 
and Week 6. Compliance rates during the treatment period will be derived using the 
following formula: 
100*((Total number of capsules taken) / (Expected number of capsules to be taken), 
where “Total number of capsules taken” will be derived separately for the intervals 
Baseline to Week 6 and for Week 6 to Week 12/EOT and is calculated as the total 
number of capsules dispensed minus the total number of capsules returned from the 
corresponding drug kit. The total number of capsules taken on study will be derived 
as the sum of the total capsules taken from the two intervals. Total number of 
capsules taken will be missing for an interval based on drug dispensation if drug kit is 
dispensed but not returned or is lost. In such cases, total number of capsules taken for 
the interval will be derived based on the study medication diary, where the “Total 
number of capsules taken” will be derived as the sum of the total number of capsules 
reported to have been taken each study day in the interval, with missing diary dates 
treated as 0 capsules taken. Complete derivation details will be provided in the 
ADaM specifications. 
Expected number of capsules to be taken is based on the date of first study 
medication dose and the date of last study medication dose and the subject’s weight 
range band at screening that determines the number of capsules expected to be taken 
at each study week, following the expected daily dosing and titration schedule (see 
protocol section 5.1) 
Descriptive statistics will be displayed for total number of capsules taken, expected 
number of capsules taken, and compliance rate. Compliance rates will also be 
presented using frequency and percentages for the categories 0% to <20%, 20% to 
40%, 40% to <60%, 60% to <80%, 80% to <=100%, >100% to ≤120%, or >120% by 
treatment group and overall. 
All study drug exposure and compliance information will be presented in subject 
listings. All study drug titrations, study drug accountability, study medication taken 
daily diary information, and study medication overdoses will also be presented in by- 
subject listings. 
 
3.8 Efficacy Analyses 
All efficacy analyses will be based on the FAS. Additionally, the analysis of the 
primary endpoint will be repeated on the PPS to assess the sensitivity of the results to 
major protocol violations. All efficacy variables will be summarized descriptively by 
treatment group and visit, including observed, change from baseline, and percent 
change from baseline, if appropriate. Sensitivity analyses to assess the impact of 


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missing primary endpoint data will be conducted on the FAS analysis set and are 
described below. 
 
3.8.1 Primary Efficacy Endpoint Analyses 
The CGI-I-AS scale assessed by the clinician will be collected at Week 6 and 12 
visits. This is an ordinal variable with scores ranging from 1 (very much improved), 
4 (no change), to 7 (very much worse) which will be analyzed as a continuous/ordinal 
outcome variable in these analyses. The normality of CGI-I-AS at Week 6 and Week 
12 for each treatment group will be examined. The examination of CGI-I-AS at each 
visit to ascertain the degree of departure from normality will involve generating bar 
charts, histograms, box-plots and normal probability plots, to visually evaluate the 
skewness and the kurtosis of the CGI-I-AS Week 6 and Week 12 data. 
Descriptive statistics will be displayed for CGI-I-AS total improvement score at each 
visit by treatment group for the FAS. Frequencies and percentages will also be 
tabulated for the number of subjects with each specific score, the number of subjects 
with a response of at least minimally improved, and the number of subjects with a 
response of at least much improved by treatment group and overall. A response of at 
least minimally improved is defined as a CGI-I-AS score of 1, 2, or 3. A response of 
at least much improved is defined as a CGI-I-AS score of 1 or 2. 
A separate summary will also be displayed for CGI-I-AS total improvement score at 
each visit for each age group at randomization (4 to 8 years or 9 to 12 years) within 
treatment group and all age groups combined within treatment group. The 95% CIs 
will be calculated for the mean difference in the CGI-I-AS total improvement score by 
week and age group for OV101 versus placebo. Frequencies and percentages will also 
be tabulated for the number of subjects with each specific score, the number of 
subjects with a response of at least minimally improved, and the number of subjects 
with a response of at least much improved by age group within treatment group and 
all age groups combined within treatment group. 
Descriptive statistics will also be displayed for CGI-I-AS total improvement score at 
each visit by treatment group, separately for each stratification region (US, outside 
US). An additional table displaying CGI-I-AS total improvement score at each visit 
by treatment group, separately for each country will also be presented. 
In addition, a separate summary will also be displayed for CGI-I-AS total 
improvement score at each visit for each method of CGI-I-AS assessment. For this 
analysis, subjects will be grouped into the remote/phone visit collection group if any 
CGI-I-AS assessment is conducted remotely and into the on-site visit collection group 
if none of the CGI-I-AS assessments are conducted remotely. 


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As the primary analysis, a Mixed Model Repeated Measures (MMRM) Analysis of 
Variance (ANOVA) model will be fitted using restricted maximum likelihood 
(REML) for CGI-I-AS with fixed effects for visit (Weeks 6 and 12), randomized 
treatment, the visit-by-treatment interaction, age group (randomization stratification 
variable: age 4 to 8 years versus age 9 to 12 years), and region (randomization 
stratification variable: US versus outside US) for the FAS. An unstructured within 
subject-covariance structure is preferred and will be specified first. If the model 
converges, the Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. 
If the model with unstructured covariance fails to converge, the following covariance 
structures will be tested in this order: toeplitz with heterogeneity, autoregressive with 
heterogeneity by visit, compound symmetry with heterogeneous variances by visit, 
toeplitz, autoregressive, and compound symmetry without heterogeneous variances 
by visit. The first covariance structure that converges will be used for the analysis. If 
a structured covariance is used, then a robust sandwich estimator will be utilized for 
estimating the variance of the treatment effect estimate. 
From the model, the Week 12 difference between least squares means of OV101 and 
placebo groups will be presented along with the corresponding 95% confidence 
interval and 2-sided P-value. This analysis will be repeated for the PPS. 
Furthermore, as an additional supportive analysis, this analysis will also be repeated 
based on method of CGI-I-AS assessment collection (remote/phone or on-site) as 
described above. 
As supportive analysis, an ANOVA on the Week 12 data will be performed (observed 
case analysis) for the FAS and PPS with effects for randomized treatment, age group, 
and region. 
As sensitivity analysis of the normality assumption for Week 12 CGI-I-AS data, a 
Wilcoxon rank sum exact test, with a continuity correction of 0.5, will be used for 
treatment group comparison of Week 12 CGI-I-AS scores for the FAS and PPS. The 
2-sided exact p-value will be presented. The Hodges–Lehmann estimate of the 
median CGI-I-AS difference between OV101 and placebo groups, and its 95% 
confidence interval will also be presented. 
If more than 3% of CGI-I-AS values at Week 12 are missing, a sensitivity analysis 
involving multiple imputation will be conducted. Additionally, if more than 5% of 
CGI-I-AS values at Week 12 are missing, a tipping point analysis will be also 
performed. Details are specified in the Section 3.8.6. 
In addition to the supportive analyses mentioned above, an additional supportive 
analysis will be conducted in which CGI-I-AS assessments from unscheduled visits 
and end of treatment (EOT) visits from subjects discontinuing treatment early (before 


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Week 12) will be mapped using alternative visit window mapping (see Table 3 
section 3.1.8). 
For this analysis, descriptive statistics will be displayed for CGI-I-AS total 
improvement score at each visit by treatment group for the FAS. Frequencies and 
percentages will also be tabulated for the number of subjects with each specific score, 
the number of subjects with a response of at least minimally improved, and the 
number of subjects with a response of at least much improved by treatment group and 
overall. 
An MMRM ANOVA methodology similar to the one described above will also be 
performed after mapping the CGI-I-AS assessments using the alternative visit 
mapping (Table 3). From the model, the Week 12 difference between least squares 
means of OV101 and placebo groups will be presented along with the corresponding 
95% confidence interval and 2-sided P-value. 
An additional supportive analysis will be conducted in which CGI-I-AS assessments 
will be analyzed according to the nominal visit time point as defined in section 3.1.8. 
Descriptive statistics will be displayed for CGI-I-AS total improvement score at each 
visit by treatment group for the FAS. An MMRM ANOVA analysis as described 
above will also be presented. 
3.8.2 Key Secondary Efficacy Endpoint Analyses 
A generalized logit model will be used for the analysis of key secondary endpoints: 
CGI-I-AS response (at least minimally improved) and CGI-I-AS response (at least 
much improved). The generalized logit models will include the response variable at 
each visit as the dependent variable, and fixed effects for visit (Week 6 and Week 12), 
randomized treatment, the visit-by-treatment interaction, age group (randomization 
stratification variable: age 4 to 8 years versus age 9 to 12 years), and region 
(randomization stratification variable: US versus outside US). An unstructured 
Cholesky working correlation for the binary outcome variable will be assumed for the 
model parameter estimation, and if the model fails to converge, the sequence of 
covariance structures specified in Section 3.8.1 will be used, until convergence is 
achieved. If there is no response (at least minimally improved or at least much 
improved) in either treatment arm at the Week 6 visit, the generalized logit model will 
be substituted with a logistic regression for the Week 12 CGI-I-AS response variable 
with effects for the randomized treatment and the two randomization stratification 
variables. From the model (generalized logit or logistic regression, as appropriate), 
the Week 12 odds ratio will be presented along with the corresponding 95% 
confidence interval and 2-sided P value. 
Descriptive statistics for the observed response (either at least minimally improved or 
at least much improved) will also be displayed along with the 95% CI based on a 


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sleep efficiency)
 
 
binomial distribution. In addition, the differences in observed percentages between 
treatment groups will be displayed, along with the corresponding 95% CI for 
differences in percentages and two-sided p-value. 
Sensitivity analyses will be conducted based on method of assessment collection (at 
least one CGI-I-AS assessment conducted remotely or no CGI-I-AS assessment 
conducted remotely). Descriptive statistics and a subgroup analysis of the 
generalized logit analysis described above will be performed. 
Additionally, supportive analyses will be performed for the descriptive analysis and 
generalized logit model with the visit mapping described in section 3.1.8 Table 3 and 
separately for visit mapping using nominal visits. 
 
3.8.3 Other Secondary Efficacy Endpoint Analyses 
For each subject, the average of daily values for each actigraphy variable (LSO and 
will be calculated for the following visit windows:  
Table 4: Analysis Visit Windows for Actigraphy Endpoints 
 
Assessment
Analysis Visit Window (Interval in Study Days)
Baseline
< Day 1
Week 6 
≥ (Week 6 Visit date – 14 days) to ≤ (Week 6 Visit Date + 7 days); or 
≥ Day 22 to ≤ (End of Treatment – 1 day), for subjects who early 
terminate before Week 6 
Week 12 
≥ (Week 12 Visit date – 14 days) to (Week 12 Visit Date - 1 day); or 
≥ Day 65 to ≤ (End of Treatment – 1 day), for subjects who early 
terminate between Week 6 and Week 12 
An average measure will be calculated using all available data in the above analysis 
windows as follows: 
1. Calculate average of all observed weekday values (AVGWKD).  
2. Calculate average of all observed weekend values (AVGWKE). 
3. Within a visit, if both AVGWKD and AVDWKE are non-missing, then 
the final average for the visit is AVGWKD*(5/7) + AVGWKE*(2/7). 
4. Otherwise, the final average for the visit is set to the non-missing 
AVGWKD or AVGWKE. 
An MMRM Analysis of Covariance (ANCOVA) model for the change from Baseline 
will be fitted for each actigraphy endpoint defined above with fixed effects for visit 
(Weeks 6 and 12), randomized treatment, the visit-by-treatment interaction, age group 
(randomization stratification variable: age 4 to 8 years versus age 9 to 12 years), 
region (randomization stratification variable: US versus outside US), and the 
corresponding Baseline as a covariate. An unstructured within-subject covariance 
structure will be specified as the first choice. If the model converges, the Kenward- 
actigraphy 
h actigraphy variable (LSO and 
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Roger approximation will be used to estimate the denominator degrees of freedom. 
If the model with unstructured covariance fails to converge, the following covariance 
structures will be tested in this order: toeplitz with heterogeneity, autoregressive with 
heterogeneity by visit, compound symmetry with heterogeneous variances by visit, 
toeplitz, autoregressive, and compound symmetry without heterogeneous variances 
by visit. The first covariance structure that converges will be used for the analysis. If 
a structured covariance is used, then a robust sandwich estimator will be utilized for 
estimating the variance of the treatment effect estimate. From the model, the Week 12 
difference between least squares means of OV101 and placebo groups will be 
presented along with the corresponding 95% confidence interval and 2-sided P-value. 
Based on the visit average values, if more than 5% but not more than 20% of any 
actigraphy secondary endpoint are missing at Week 12, a sensitivity analysis will be 
conducted. Details are specified in Section 3.8.6. 
An additional sensitivity analysis may be performed if visit average values at Weeks 6 
or 12 are based on less than 3 days of data. In this scenario, only subjects whose visit 
average values are based on a minimum of 3 days of data (either weekday or 
weekend) will be included. 
The VABS-3 Total Score (Adaptive Behavior Composite Score), domain standard 
scores (Communication, Socialization, Daily Living Skills, and Motor Skills 
domains) and their subdomain raw scores, including the Maladaptive Behavior 
domain subscale scores, will be assessed at Baseline and Week 12 and analyzed as 
continuous outcome variables. When corresponding subdomain Growth Scale Value 
(GSV) scores or v-Scale scores are available, the GSV and v-Scale scores will also be 
analyzed as a sensitivity analysis. 
Change from Baseline to Week 12 in VABS-3 standard/raw score will be analyzed 
using an ANCOVA model with effects for randomized treatment, age group 
(randomization stratification variable: age 4 to 8 years versus age 9 to 12 years), 
region (randomization stratification variable: US versus outside US), and the 
corresponding Baseline as a covariate. A test for a significant treatment-by-baseline 
interaction will be performed in a separate model (including the above terms plus the 
interaction term), using a 0.100 alpha level. If the treatment-by-baseline interaction is 
significant, then the ANCOVA assumptions are violated and an ANOVA model will 
be used instead. From the final model, the difference between least squares means of 
OV101 and placebo groups will be presented along with the corresponding 95% 
confidence intervals and 2-sided P-values. 
When it is available, change from Baseline to Week 12 in VABS-3 GSV scores will 
be analyzed using the same method described above. Individual VABS-3 item scores 
and its shift from baseline at scheduled visits will be summarized in exploratory 
analysis. 
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3.8.4 Tertiary and Exploratory Efficacy Endpoints
 
 
Scatterplots to assess correlation between VABS-3 Total Score with CGI-S-AS 
overall at each visit (Baseline and Week 12), and change from Baseline to Week 12 in 
VABS-3 Total Score with change from Baseline to Week 12 CGI-S-AS will also be 
explored. 
The CGI-S-AS assessment will be collected at Baseline, Week 6, and Week 12 and 
will be treated as a continuous outcome variable. An MMRM ANCOVA 
methodology similar to the one described previously for actigraphy variables will be 
used to analyze the change from Baseline in CGI-S-AS score. 
The relationships between CGI-S-AS overall score at baseline and CGI-I-AS at Week 
12 will be explored through calculation of Pearson correlation coefficient and the 
associated CI within each treatment group accompanied by the corresponding 
scatterplot to aid interpretation of the correlation. The relationships between each of 
CGI-S-AS domain scores at baseline and CGI-I-AS at Week 12 will also be explored 
using a similar approach. 
 
 
 
 
 
 
Assessment  
Analysis Visit Window (Interval in Study Days)  
Baseline  
≤Day 1  
Week 6  
≥ (Week 6 Visit date – 14 days) to ≤ (Week 6 Visit Date + 7 days);  
 
or  
≥Day 22 to ≤(End of Treatment), for subjects who early terminate  
before Week 6  
Week 12  
≥ (Week 12 Visit date – 14 days) to (Week 12 Visit Date); or  
 
≥Day 65 to ≤(End of Treatment), for subjects who early terminate  
between Week 6 and Week 12
 
The average calculation described above for actigraphy variables (LSO and sleep 
efficiency) will be applied to the additional actigraphy parameters and sleep diary 
variables. An MMRM ANCOVA methodology will be applied to the change from 
Baseline endpoint as described previously for actigraphy endpoints. 
The CSHQ will be collected at Baseline/Day 1, Week 6, and Week 12, and will be
treated as a continuous outcome variable. An MMRM ANCOVA methodology  
similar to the one described previously for actigraphy endpoints will be used to
Table 5: Analysis Visit Windows for Sleep Diary Endpoints
The actigraphy total sleep time at night, total daytime sleep, and daily activity level 
endpoints and sleep diary endpoints will be collected at Baseline, Week 6, and Week 
12 and analyzed as continuous outcome variables. An average of daily values for 
each sleep diary endpoint will be calculated for the following visit windows (note that 
the date of the sleep diary record refers to details collected the night before): 
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waking/daytime sleepiness).
around night wakings, parasomnias, sleep-disordered breathing, and morning
resistance, sleep-onset delay, sleep duration, anxiety around sleep, behavior occurring
analyze the change from Baseline in CSHQ Total and Subscale scores (bedtime
The Peds QL assessment will be collected at Baseline/Day 1 and Week 12, and the 
total and dimension scores will be treated as continuous outcome variables. For each 
dimension scale, an ANCOVA methodology will be applied to the change from 
Baseline to Week 12 endpoint as described previously for VABS-3 endpoints. 
Baseline.
described previously for actigraphy endpoints will be used to analyze the change from
variables. For each subscale, An MMRM ANCOVA methodology similar to the one
11, Week 6, Week 12, and Week 14, and will be treated as continuous outcome
ABC-C subscale scores (excluding ABC-I) will be collected at Baseline, Day 6, Day 
 
 
 
 
 
3.8.5 Subgroups to be Analyzed 
Descriptive statistics will be presented separately by age group (randomization 
stratification variable: age 4 to 8 years versus age 9 to 12 years) for the primary and 
the two key secondary endpoints. Observed values will be reported by treatment 
group. The difference in means or proportions for OV101 versus placebo will also be 
presented with the corresponding 95% confidence intervals. Similar subgroup 
analysis will be conducted for region (US versus outside US). 
If for a given endpoint, the results in the two subgroups appear different from a 
clinical perspective, the appropriate model (MMRM, generalized logit, or logistic) 
could be constructed as described above, including an age-by-treatment interaction 
term. This interaction term will be tested at alpha level of 0.100 to assess whether the 
treatment effects are statistically significantly different for the two age subgroups. 
 
3.8.6 Missing Data Handling and Sensitivity Analysis 
All analyses involving imputation of missing efficacy data will be accompanied with 
a descriptive table showing the number and percentage of missing endpoint values by 
visit and treatment group. The reasons of missing, if captured, will be also displayed. 
Primary Analysis – CGI-I-AS 
The primary endpoint, CGI-I-AS scale assessed by the clinician will be collected at 
the Week 6 and 12 visits. This is an ordinal variable with scores ranging from 1 (very 
much improved), 4 (no change), to 7 (very much worse) which will be analyzed as a 
continuous outcome variable in the analyses. 
For the primary analysis of CGI-I-AS, missing data will not be imputed. The primary 
analysis will be based on all available data at the mapped visits (Table 2) at Week 6 


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and Week 12 as captured in the clinical database, using a MMRM ANOVA model 
with fixed effects for visit (Weeks 6 and 12), randomized treatment, the visit-by- 
treatment interaction, and age group (randomization stratification variable: age 4 to 8 
years versus age 9 to 12 years) and region (randomization stratification variable: US 
versus outside US). MMRM models implicitly adjust for missing data under a 
missing at random (MAR) assumption. 
Sensitivity Analyses Using Multiple Imputation – CGI-I-AS 
If more than 3% of CGI-I-AS values at Week 12 are missing, as a sensitivity analysis, 
missing data will be imputed using the multiple imputation (MI) procedure. The 
imputation strategy described in Ouyang (2017) will be implemented for this study. 
There are only two visits where CGI-I-AS is assessed, hence, there are 2 possible 
missing patterns in the CGI-I-AS data: 1) Week 6 assessment is missing and Week 12 
assessment is present (non-monotone pattern); or 2) Week 12 assessment is missing 
but Week 6 assessment is present (monotone pattern). In general, the MAR 
assumption is reasonable for intermittent missing values before a subject is 
discontinued because the data before and after the intermittent missing value are 
known. In this case, if Week 6 CGI-I-AS is missing but Week 12 CGI-I-AS is 
assessed (missing data pattern 1), it is reasonable to consider the missing Week 6 data 
as MAR. However, missing CGI-I-AS at Week 12 after the subject is withdrawn 
from the trial may or may not be MAR. Multiple imputation will first be 
implemented under the MAR assumption. To assess the appropriateness of the MAR 
assumption, additional sensitivity analyses using a tipping point approach will be 
performed under scenarios assuming missing not at random (MNAR) for the missing 
data pattern 2 above. 
Multiple Imputation Procedure under MAR assumption will be conducted as follows 
using SAS PROC MI: 
1. Missing Week 6 CGI-I-AS data points will be imputed under MAR assumption 
using a logistic regression model for ordinal data with randomized treatment, age 
group, region, and CGI-S-AS Overall Score at Baseline as independent variables. 
2. Missing Week 12 CGI-I-AS data points will be imputed under MAR assumption 
using a logistic regression model for ordinal data with randomized treatment, age 
group, region, CGI-S-AS Overall Score at Baseline, and the Week 6 CGI-I-AS as 
independent variables. 
3. Thirty complete imputed datasets will be generated by repeating the above steps 30 
times. 
4. The primary MMRM analysis of CGI-I-AS described above will be performed for 
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Main Analyses of Actigraphy Endpoints
 
 
5. The estimated treatment effects will be combined across the 30 analyses using SAS 
PROC MIANALYZE. 
If the treatment effect is significant in the analysis using the MI procedure under 
MAR, with significance level of 0.05 and more than 5% of CGI-I-AS values at Week 
12 are missing, a tipping point analysis will be conducted. 
The tipping point analysis will focus on the imputed CGI-I-AS values which may be 
MNAR (missing data pattern 2 above). These analyses will start with the 30 imputed 
datasets created under a MAR assumption as described above. For each dataset, the 
imputed values of CGI-I-AS for the OV101 group (with missing pattern 2) will be 
worsened by adding 1 (unless the current value is the highest level on the CGI-I-AS 
scale [7=very much worse]). The placebo group imputed values will remain 
unchanged. After the OV101 group’s imputed Week 12 CGI-I-AS data have been 
“worsened” by 1 point for those with missing pattern 2, the MMRM model used in the 
primary analysis will be fitted to the data and the estimated treatment effects will be 
combined using SAS PROC MIANALYZE. This process will be repeated, at each 
step incrementally worsening by 1 the imputed values of CGI-I-AS for the OV101 
group, until the treatment effect is no longer significant (p-value for the treatment 
comparison ≥0.05). 
As a sensitivity analysis, the following rank-based imputation strategy described in 
Ouyang (2017) will also be implemented when more than 5% of CGI-I-AS values at 
Week 12 are missing. This analysis will include both subjects with a Week 12 CGI-I- 
AS and subjects who discontinued prior to the Week 12 assessment, without the need 
for multiple imputation methodology and the associated assumptions. This approach 
assumes that discontinuation from the trial is detrimental so it penalizes the treatment 
group with more early discontinuations. The subjects will be first divided into 2 sets 
according to their CGI-I-AS assessments: 1) those with a Week 12 CGI-I-AS; and 2) 
those with a Week 6 CGI-I-AS but no Week 12 CGI-I-AS. Within the two sets, 
subjects will be ranked separately (based on the Week12 CGI-I-AS for set 1 and the 
Week 6 CGI-I-AS for set 2). The lowest rank will be given to the largest CGI-I-AS 
within that set. The Wilcoxon Rank-Sum test will then be applied to this ranking 
instead of ranking solely based on the Week 12 CGI-I-AS for completers. 
 
As described in Section 3.8.3, MMRM Analysis of Covariance (ANCOVA) models 
for the change from Baseline will be fitted for each actigraphy endpoint with fixed 
effects for visit (Weeks 6 and 12), randomized treatment, the visit-by-treatment 
interaction, age group, region, and the corresponding Baseline as a covariate. Missing 
data will not be imputed in the main analyses, but MMRM models implicitly adjust 
for missing data under a missing at random (MAR) assumption. 
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actigraphy
 
 
 
Based on visit average values, if more than 5% but not more than 20% of actigraphy 
data are missing at Week 12, as sensitivity analyses for each actigraphy secondary 
endpoint, missing data will be imputed using a multiple imputation procedure under a 
MAR assumption as follows:  
1. Missing Week 6 actigraphy data points will be imputed under a MAR assumption 
using a linear regression model with randomized treatment, age group, region,  and 
the corresponding baseline as independent variables. 
2. Missing Week 12 actigraphy data points will be imputed under MAR assumption 
using a linear regression model with randomized treatment, age group, region, and the 
corresponding baseline and Week 6 actigraphy variable as independent variables. 
3. Thirty complete imputed datasets will be generated by repeating the above steps 30 
times. 
4. The primary MMRM analysis of each actigraphy endpoint as described above will 
be performed for each of the 30 complete imputed data sets. 
5. The estimated treatment effects will be combined across the 30 analyses using SAS 
PROC MIANALYZE. 
If there is more than 20% of data missing for actigraphy endpoints, then baseline 
characteristics (including Baseline CGI-S-AS) will be compared for the subjects 
missing the specific 
endpoint versus the subjects who are not missing the 
specific actigraphy endpoint, for both treatment groups combined. In this analysis, 
Baseline CGI-S-AS will be summarized as a continuous variable, with the focus on 
the mean if the normality assumptions are met for Baseline CGI-S-AS, and the focus 
on the median if Baseline CGI-S-AS is non-normal. Also, if the prevalence of missing 
is similar across treatment groups, CGI-I-AS at Week 12 will also be summarized by 
missing status and treatment group. These analyses will inform the interpretation of 
the descriptive analysis of the actigraphy endpoints.  
 
3.9 Safety Analysis 
All safety analyses will be based on the SS. Descriptive statistics will be used to 
summarize all safety endpoints by treatment group. Data summaries will be displayed 
for incidence of TEAEs, clinical laboratory variables, vital signs, body weight and 
body mass index, physical examinations, clinical assessment of suicidality (ABC-I) 
and seizure diary data. 
Unless otherwise specified below, safety data for subjects 2 to 3 years old (inclusive) 
will only be presented in listings and will be displayed in by-subject graphs, as 
appropriate. 
Sensitivity Analyses Using Multiple Imputation – Actigraphy
actigraphy 
actigraphy e
actigraphy e
p
actigraphy 
g
p
actigraphy 
actigraphy v
actigraphy 
actigraphy 
f actigraphy


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3.9.1 Adverse Events 
All adverse events will be coded using the MedDRA Version 22.0 and will be 
classified by MedDRA SOC and PT. Analyses of adverse events will be performed 
using the SS. 
AEs that started on or after the first dose of study medication or worsened after the 
first dose of study medication through 14 days after the last dose of study medication 
and 30 days after the last dose of study drug/last study visit for SAEs are considered 
treatment-emergent AEs (TEAEs). 
For all summaries, SOCs and PTs within SOC will be presented by decreasing 
frequency of incidence, sorted first for the OV101 group and then for the placebo 
group. 
Handling of Missing or Partial Start Dates for Adverse Events 
Rules for handling incomplete or missing adverse event start dates are addressed 
below (stop dates will not be imputed). 
In the unusual case that the month portion of an adverse event start date is missing but 
the day portion is not missing, the day portion will be assumed to be missing. 
Likewise, in the case where the year portion of an adverse event start date is missing 
but the month and/or day portion is not missing, the month and/or day portion will be 
assumed to be missing. All missing portion(s) of the date will be handled using the 
same rules: 
 In the event that the day portion (and only the day portion) of the date is 
missing: 
o If the adverse event started in the same month and year as the first 
dose date, the adverse event start date will be assumed to be the first 
dose date. 
o Otherwise, the adverse event start date will be assumed to be the last 
day of the given month and year, e.g., XX–DEC-2005 would be 31- 
DEC-2005 where XX represents an unknown day. 
 In the event that the day and month portions (and only the day and month 
portions) of the date are missing: 
o If the adverse event started in the same year as the first dose date, the 
adverse event start date will be assumed to be the first dose date. 
o Otherwise, the adverse event start date will be assumed to be last 
month and day of the given year, e.g., XX–XXX-2005 would be 31- 
DEC-2005 where XX represents an unknown day and XXX represents 
an unknown month. 


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 In the event that the day, month, and year portions of the adverse event start 
date are missing, it will be assumed to be the first dose date. 
 If the adverse event start date has been imputed using the rules above, then the 
adverse event start date must be compared with the adverse event stop date to 
ensure the logical ordering of dates. If the imputed adverse event start date is 
after the non-missing adverse event stop date, then the imputed start date will 
be reset as the stop date. 
 
3.9.1.1 Overall Summary of AEs 
An overall summary of TEAEs will be presented by treatment group. The number 
and percentage of subjects who experienced at least one TEAE, at least one mild 
TEAE, at least one moderate TEAE, at least one severe TEAE, at least one TEAE 
leading to dose change/interruption, at least one TEAE leading to study drug 
discontinuation, at least one TEAE leading to study withdrawal, at least one 
treatment-related TEAE, at least one serious TEAE, at least one treatment-related 
serious TEAE, and a TEAE leading to death will be displayed. Treatment-related 
TEAEs are events with a study drug causality of ‘possible’, ‘probable’ or ‘definite.’ 
Incidence of AEs will be summarized separately for subjects 2 to 3 years old 
(inclusive). 
 
3.9.1.2 AE Incidences 
The incidence of TEAEs will be presented by actual age group (4-8 versus 9-12 years 
old) and treatment group. The number and percentage of subjects who experienced at 
least one TEAE as well as the number and percentage of subjects who experienced 
each specific SOC and PT will be presented. For this analysis, if a subject has more 
than one occurrence of the same PT, then the PT will be counted only once for that 
subject. Similarly, if a subject has more than one occurrence of the same PT within a 
SOC, the subject will be counted only once in that SOC. 
A summary table by PT only will be presented using the same methods as described 
above for the by SOC and PT summary table. Additionally, the incidence of TEAE 
within each specific SOC, HLGT, and PT and specific SOC, HLT, and PT will be 
presented. The incidence of TEAEs by SOC/PT and maximum severity will also be 
presented. 
For subjects 2 to 3 years old, a summary table by SOC and PT, by PT, and the 
incidence of TEAEs by PT and maximum severity will be presented. 
All TEAEs will be included in a subject listing. 


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3.9.1.3 Related AEs 
The incidence of drug-related TEAEs will be presented by actual age group (4-8 
versus 9-12 years old) and treatment group. Related TEAEs will be defined as those 
with a ‘possible’, ‘probable’ or ‘definite’ relationship to treatment. TEAEs with 
missing relationship will be counted as related. For this analysis, if a subject has 
more than one occurrence of the same PT, then the PT will be counted only once for 
that subject. Similarly, if a subject has more than one occurrence of the same PT 
within a SOC, the subject will be counted only once in that SOC. 
A summary table of drug-related TEAEs will also be presented for subjects 2 to 3 
years old. These tables will be repeated for drug-related serious AEs. 
 
3.9.1.4 Deaths, Other Serious AEs and AEs That Led to Treatment 
Discontinuation 
Summaries of deaths, other serious AEs, and AEs that led to treatment 
discontinuation will be presented by actual age group (4-8 versus 9-12 years old) and 
treatment group. A summary of serious AEs, and AEs that led to treatment 
discontinuation will also be presented for subjects 2 to 3 years old. Adverse events 
that led to study withdrawal will be shown in a listing. 
 
3.9.1.5 AEs That Led to Study Drug Interruption 
All adverse events that resulted in study drug interruption will be included in a by- 
subject listing. 
 
3.9.1.6 AEs of Special Interest 
Adverse events of special interest include the following categories: 
 Sleep Disorders and Disturbances (HLGT) 
 Seizures (Including Subtypes) (HLGT) 
 
All AEs of special interest will be identified by using the above MedDRA PTs during 
a blinded review of the data. 
The incidence of TEAEs of special interest by actual age group (4-8 versus 9-12 years 
old) and treatment group will be presented separately for each term. The number and 
percentage of subjects who experienced at least one TEAE of special interest as well 
as the number and percentage of subjects who experienced each specific SOC and PT 
will be presented. For this analysis, if a subject has more than one occurrence of the 
same PT, then the PT will be counted only once for that subject (e.g., subject 
incidence). Similarly, if a subject has more than one occurrence of the same PT 
within a SOC, the subject will be counted only once in that SOC. 


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3.9.2 Clinical Laboratory Evaluation 
A list of clinical laboratory tests is given below: 
 
Hematology 
- Hematocrit 
- Hemoglobin 
- Red blood cell count 
- Mean corpuscular volume 
- Mean corpuscular hemoglobin 
- Mean corpuscular hemoglobin 
concentration 
- Reticulocytes 
- White blood cell count 
- Neutrophils (% and count) 
- Lymphocytes (% and count) 
- Monocytes (% and count) 
- Eosinophils (% and count) 
- Basophils (% and count) 
- Platelet count 
- Prothrombin time 
- Partial thromboplastin time 
- International normalization ratio 
Clinical 
Chemistry 
- Albumin 
- Alkaline phosphatase 
- Blood urea nitrogen 
- Gamma-glutamyl transferase 
- Calcium 
- Creatinine 
- Glucose 
- Cholesterol, high-density 
lipoprotein [calculated] 
- Cholesterol, low-density 
lipoprotein [calculated] 
- Cholesterol, homogenous low- 
density lipoprotein 
- Triglycerides 
- Magnesium 
- Phosphate 
- Potassium 
- Alanine aminotransferase 
- Aspartate aminotransferase 
- Lactate dehydrogenase 
- Sodium 
- Chloride 
- Total bilirubin 
- Direct bilirubin 
- Total protein 
- Uric acid 
- Creatine phosphokinase 
Pregnancy 
Testing1 
- Serum ß-hCG or urine pregnancy 
testing for female subjects who 
have experienced menarche 
 
1 Pregnancy testing parameter will be listed only. 
Continuous laboratory data will be examined for trends using descriptive statistics of 
observed values and changes from baseline to each planned post-baseline visit. These 
data will also be categorized as low, normal or high based on the reference ranges of 
the central/local laboratory. Frequencies and percentages will be presented for the 
shifts in these categories from baseline to each post-baseline visit (i.e., low to normal, 
low to high, high to low, etc.) for all applicable laboratory parameters listed above. 
The analyses will be performed using the SS and presented by treatment group. 
A separate listing for all clinically significant laboratory abnormalities will be 
provided. 
 
3.9.3 Vital Signs and Other Physical Findings 
Vital signs (temperature, heart rate, respiratory rate, and systolic and diastolic blood 
pressure), weight, and body mass index will be summarized descriptively at Baseline 
and all post-Baseline study visits by treatment group. Values will be categorized 


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for all PK analyses.
The pharmacokinetic analyses will be performed by Synteract. The PKS will be used
will subsequently be subjected to population PK modeling and resulting exposure
At the end of the study, OV101 concentration and time data obtained from this study 
 
 
based on reference ranges by age group as normal, low abnormal, and high abnormal 
(see section 4.1.8). Shift from Baseline to all post-Baseline study visits for these 
categories will be summarized descriptively by treatment group. 
All vital sign results will be included in a subject listing. 
 
3.9.4 Physical Examination 
Physical examinations (general appearance; skin; head, ear, eye, nose, and throat; 
neck; lymph node; chest; heart; abdominal cavity; limb; central nervous system; and 
musculoskeletal) will be performed. 
Whether or not a physical examination was conducted with date performed will be 
included in a subject listing. 
 
3.9.5 Assessment of Suicidality 
ABC-Irritability (ABC-I) subscale scores (Aman et al., 1985) will be summarized 
descriptively at Baseline and all post-Baseline study visits by treatment group. 
Change from Baseline and percent change from Baseline to all post-baseline study 
visits will also be summarized descriptively by treatment group. The Aberrant 
Behavior Checklist – Community (ABC-C) Baseline Record Form version 23Apr2018 
and the Follow Up Record Form version 20Apr2018 will be implemented. 
All ABC-I assessment results will be included in a subject listing. 
 
3.9.6 Seizure Diary Data 
The number of subjects reporting a new type of seizure during treatment and the type 
of new seizures reported during treatment will be summarized. Additionally, the 
seizure frequency per 28 days (normalized) will be calculated for the following study 
periods: Baseline (Screening to Day -1), Week 6 (Day 1 to Week 6 visit date or EOT 
before Day 43), and Week 12 (Week 6 visit date + 1 day to Week 12 visit date or 
EOT between Day 44 and Day 85). Percent change in seizure frequency per 28 days 
from Baseline to all post-baseline study visits also will be summarized descriptively 
by treatment group. 
All seizure diary results will be included in a subject listing.  
 
3.10 
 
 
Pharmacokinetic Analyses


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old at various weight bands.
confirm predicted exposure estimates for the pediatric study population 2 to 12 years
estimates will be compared to values derived from a validated PBPK modeling to
The population PK exposure values and predicted exposure estimates from the PBPK 
model specific for OV101 will be compared to extant PK data from adult and 
adolescent subjects. The PBPK model and simulations are based upon known 
OV101-related physicochemical, formulation, and absorption, distribution, 
metabolism, and excretion data as well as appropriate age -specific adult and pediatric 
anatomy, developmental and physiologic data (including body weight, composition, 
organ size, blood flow, tissue perfusion, protein binding, transporter/enzyme 
expression as well as age-related hepatic, and renal function estimates). The PBPK 
modeling details will be reported separately. In addition to Cmax and AUC exposure 
estimates, elimination half-life and tmax values may also be estimated.
will be treated as missing.
coefficient of variation. Plasma concentrations below the lower limit of quantification
The descriptive statistics to be presented will include geometric mean and geometric
OV101 plasma concentrations will be summarized descriptively at each timepoint.
coefficients of variation will be presented.
parameters (if derived) will be summarized descriptively and geometric means and
The population PK-derived exposure estimates (Cmax and AUC) and other
4.1.2 Actigraphy
 
 
 
 
 
 
3.11 Interim Analysis 
No interim analyses of efficacy data are planned for this study. 
 
4 DATA HANDLING 
4.1 Derived Endpoints and Data Handling 
4.1.1 Handling of Repeated Assessments 
If multiple results are reported for an assessment at the same post-baseline visit, then 
the first record will be used in analysis.  
 
 
 
time put to bed and time got out of bed reported on the sleep diary.
visit. The time to bed and the rest period (total time in bed) will be determined from
Below are the derivations needed to generate one summary value per subject for each
At each visit, all subjects will have actigraphy values calculated for multiple days.


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missing time got out of bed times for that subject.
missing time got out of bed will imputed as on the average of all available non-
only (and will not be used for the calculation of Sleep Efficiency). For these records,
got out of bed, time got out of bed will be imputed for the purpose of calculating LSO
bed from the sleep diary must be available. For sleep diary records with missing time
In the sleep algorithm calculation of LSO, both time put to bed and time got out of
treatment group in the FAS.
daytime sleep) will be calculated for each analysis visit window and summarized by
duration of night awakenings, number of disruptive behaviors while in bed, and
(LSO, sleep efficiency, total sleep time at night, number of night awakenings,
is scheduled to be worn. The average of daily values for each sleep diary variable
representative (LAR)/caregiver, on behalf of the subject when the actigraphy device
A paper sleep diary will be completed by each subject’s legally acceptable
 
 
Endpoint 
Derivation 
Secondary Endpoint: 
Latency of Sleep Onset 
(LSO) 
Mean of Onset Latency (minutes), duration from the 
beginning of the rest period to the start of sleep onset 
for the first sleep period of each night. 
Tertiary Endpoint: 
Total Sleep Time (TST) 
during night 
Sum of sleep time (hours) within each night, 
accounting for multiple sleep periods in a night. 
Secondary Endpoint: 
Sleep Efficiency 
Efficiency (%) is defined as total sleep time as a 
fraction of the rest period (total time in bed). 
Exploratory Endpoint: 
Daytime Sleep 
Duration of sleep time in the daytime period. 
Exploratory Endpoint: 
Daily Activity Level 
Average of activity counts/minute within each day. 
 
 
4.1.3 
 
Sleep Diary
Tertiary Endpoint:
fraction of the rest period (total time in bed). 
Sleep Efficiency 
Efficiency (%) is defined as total sleep time as a
Secondary Endpoint:
for the first sleep period of each night.
(LSO)
beginning of the rest period to the start of sleep onset 
Latency of Sleep Onset 
Mean of Onset Latency (minutes), duration from the
Secondary Endpoint:
accounting for multiple sleep periods in a night.
Sum of sleep time (hours) within each night,
during night 
Total Sleep Time (TST)
Daily Activity Level
Average of activity counts/minute within each day.
Exploratory Endpoint:
Daytime Sleep
Duration of sleep time in the daytime period.
Exploratory Endpoint:


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The CSHQ is a retrospective, 33-item caregiver questionnaire that has been used in 
studies to examine sleep behavior in young children (Owens et al 2000). The CSHQ 
includes items relating to sleep domains that encompass the major presenting sleep 
complaints in this age group, evaluating the child’s sleep based on behavior within 
eight different subscales: bedtime resistance, sleep-onset delay, sleep duration, 
anxiety around sleep, behavior occurring around night wakings, parasomnias, sleep- 
disordered breathing, and morning waking/daytime sleepiness. Caregivers will be 
asked to recall sleep behaviors occurring over the 7 days immediately preceding the 
Baseline, Week 6, and Week 12 visits. Items are rated on a 3-point scale: “usually” 
if the sleep behavior occurred 5 to 7 times/week; “sometimes” for 2 to 4 times/week; 
and “rarely” for 0 to 1 time/week. The scoring of some items can be reversed to 
consistently make a higher score indicative of more disturbed sleep. The Abbreviated 
Version (25Oct2018) will be utilized. 
reversed-scored items.
The Total Score is calculated by adding all of the item scores, accounting for the
 
 
4.1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R- reversed scored. 
follows: 
 
 
For items 32 and 33, use the highest (most problematic score indicated) score.
The CHSQ consists of 8 domains with their sub scores and will be derived as
Children’s Sleep Habits Questionnaire
Domains 
Derivation 
Bedtime Resistance 
sum of items 1R, 3R, 4, 5, 6, and 8 
Sleep Onset Delay 
item 2R 
Sleep Duration 
sum of items 9, 10R, and 11R 
Sleep Anxiety 
sum of items 5, 7, 8, and 21 
Night Wakings 
sum of items 16, 24, and 25 
Parasomnias 
sum of items 12, 13, 14, 15, 17, 22, and 23 
Sleep Disordered 
Breathing 
 
sum of item 18, 19, and 20 
 
Daytime Sleepiness 
sum of items 26R, 27, 28, 29, 30, 31, 32, and 
33 
sum of item
Sleep Disordered 
Breathing 
sum of item 18, 19, and 20
sum of items 12, 13, 14, 15, 17, 22, and 23
sum of items 16, 24, and 25
sum of items 5, 7, 8, and 21
sum of items 9, 10R, and 11R 
item 2R 
sum of items 1R, 3R, 4, 5, 6, and 8
Derivation 


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The Peds QL™ Cerebral Palsy, Multidimensional Fatigue, and Family Impact
Impact Module v2.0 (1998).
Palsy Module v3.0 (1998), Multidimensional Fatigue Scale v3.0 (1998), and Family
and family relationships. The following versions will be implemented: Cerebral
communication, and worry. It also assesses caregiver-reported family daily activities
reported assessments of physical, emotional, social, and cognitive functioning,
of pediatric chronic health conditions on caregivers and family, including caregiver-
fatigue, and cognitive fatigue. The 36-item Family Impact module assesses the impact
The 18-item Multidimensional Fatigue module assesses general fatigue, sleep/rest
and balance, pain and hurt, fatigue, eating activities, and speech and communication.
22-item Cerebral Palsy module assesses daily activities, school activities, movement
modules will be administered in this study (Varni et al 2004; Varni et al 2005). The
 
 
 
 
4.1.5 Vineland Adaptive Behavior Scales, 3rd Edition 
The VABS-3 is a standardized psychometric instrument designed to measure personal 
and social skills needed for everyday living (Sparrow et al., 2005; Sparrow et 
al., 2016). The VABS-3 is administered via a caregiver using a semi-structured 
interview format and assesses four main adaptive domains (with associated 
subdomains): communication (receptive, expressive and written), 
socialization (interpersonal relationships, play and leisure, coping skills), daily living 
skills (personal, domestic, community), and motor skills (fine and gross). It 
also includes a maladaptive behavior scale for identifying behavior problems in 
individuals ages 3 through adulthood. The scale has been found to have good internal 
consistency, test-retest reliability and validity (Sparrow et al. 2016). The VABS-3 
comprehensive interview form will be used to evaluate subjects on the 
Communication, Socialization, Daily Living Skills, Motor Skills, and Maladaptive 
Behavior domains to assess their overall adaptive functioning. QGlobal software will 
be used to calculate the summary scores. The motor skills domain standard score is 
calculated only through age 9. Higher scores for regular domain and subdomain 
scores (Communication, Socialization, Daily Living Skills, Motor Skills and 11 
subdomains) indicate better adaptive functioning. Higher scores for maladaptive 
(internalizing and externalizing scores) indicate more problem behaviors. This 
assessment is an interview with the caregiver by a trained qualified rater, and for each 
study site, the same rater is to be used throughout the study. 
 
4.1.6 
 
be imputed for that item.
subscale answers are missing. For the remaining missing values, the series mean will
Note: Total and subscale scores will not be calculated if more than 50% of the
Peds QL™
Cerebral Palsy, Multidimensional Fatigue, and Family Impact
y,
g
,
y
p
™
The Peds QL
QL™


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CEREBRAL PALSY MODULE SCORING OF DIMENSIONS:
 
 
 
 
Dimensions  
Number of  
Cluster of
Reversed  
Direction of  
 
Items  
Items  
Scoring  
Dimensions
Daily Activities 
5  
1-5  
1-5 
 
 
 
 
 
Higher scores indicate 
lower problems. 
 
 
 
Movement and  
5  
1-5  
1-5 
Balance
 
 
 
Pain and Hurt 
4 
1-4  
1-4 
 
 
Fatigue  
4 
1-4  
1-4 
 
 
 
Eating Activities 
4  
1-4  
1-4 
 
 
 
 
 
 
Item Scaling
 
5-point Likert scale from 0 (Never) to 4 (Almost always) 
Weighting of 
Items 
 
No 
Extension of the 
Scoring Scale 
 
Scores are transformed to a 0 to 100 scale. 
Scoring Procedure  
Step 1: Transform Score 
Items are reversed scored and linearly transformed to a 0- 
100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0 
Step 2: Calculate Scores by Dimensions 
x 
If more than 50% of the items in the scale are 
missing, the scale scores should not be computed, 
x 
Mean score = Sum of the items over the number of 
items answered. 
 
There is no Total score 
Interpretation and 
Analysis 
of Missing Data 
 
If more than 50% of the items in the scale are missing, the 
Scale Scores should not be computed. 
If 50% or more items are completed: Impute the mean of the 
completed items in a scale. 
DESCRIPTION OF THE 3.0 CEREBRAL PALSY MODULE: Parent Report for 
Toddlers (ages 2-4), 22 items: 
If more than 50% of the items in the scale are missing, the
Scale Scores should not be computed.
If 50% or more items are completed: Impute the mean of the
completed items in a scale.
There is no Total score
Interpretation and
Analysis
of Missing Data 
items answered.
missing, the scale scores should not be computed,
Mean score = Sum of the items over the number of 
it
d
If more than 50% of the items in the scale are
i
i
th
l
h
ld
t b
x
Step 2: Calculate Scores by Dimensions
x
100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0
St
2 C l
l t
S
b
Di
i
Items are reversed scored and linearly transformed to a 0-
f
Step 1: Transform Score
It
d
d
Item Scaling
Weighting of 
Items
Extension of the 
Scoring Scale
Scoring Procedure
Scores are transformed to a 0 to 100 scale.
5-point Likert scale from 0 (Never) to 4 (Almost always)
No 
Eating Activities
4
Higher scores indicate
lower problems.
4
Pain and Hurt 
Balance
Daily Activities
DESCRIPTION OF THE 3.0 CEREBRAL PALSY MODULE: Parent Report for 
Toddlers (ages 2-4), 22 items:


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MULTIDIMENSIONAL FATIGUE MODULE SCORING OF DIMENSIONS:
DESCRIPTION OF THE 2.0 FAMILY IMPACT MODULE: Parent Report, 36 items:
 
 
 
 
Dimensions
Number of 
Items 
Cluster of 
Items 
Reversed 
Scoring 
Direction of 
Dimensions 
General 
Fatigue 
 
6 
1-6 
 
1-6 
 
Sleep/Rest 
Fatigue 
 
6 
1-6 
 
1-6 
Higher scores indicate 
lower problems. 
Cognitive
Fatigue 
 
6
1-6
 
1-6
 
 
 
 
Item Scaling 
 
5-point Likert scale from 0 (Never) to 4 (Almost always) 
3-point scale: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for 
the Child Report for Young Children (ages 5-7) 
Weighting of 
Items 
 
No 
Extension of the 
Scoring Scale 
 
Scores are transformed on a scale from 0 to 100. 
Scoring Procedure  
Step 1: Transform Score 
Items are reversed scored and linearly transformed to a 0- 
100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. 
Step 2: Calculate Scores by Dimensions 
x 
If more than 50% of the items in the scale are 
missing, the scale scores should not be computed, 
x 
Mean score= Sum of the items over the number of 
items answered. 
 
Total Score: Sum of all the items over the number of items 
answered on all the Scales 
Interpretation and 
Analysis 
of Missing Data 
 
If more than 50% of the items in the scale are missing, the 
Scale Scores should not be computed. 
If 50% or more items are completed: Impute the mean of the 
completed items in a scale. 
 
 
 
Dimensions  
Number of  
Cluster of
Reversed  
Direction of  
 
Items  
Items  
Scoring
Dimensions
Physical  
6  
1-6  
1-6  
Higher scores indicate 
better functioning. 
Functioning  
 
 
 
 
DESCRIPTION OF THE MULTIDIMENSIONAL FATIGUE MODULE; 18 items:
Higher scores indicate
better functioning.
answered on all the Scales
If more than 50% of the items in the scale are missing, the
Scale Scores should not be computed.
If 50% or more items are completed: Impute the mean of t
completed items in a scale.
Total Score: Sum of all the items over the number of items
d
ll th
S
l
Interpretation and
Analysis
of Missing Data 
items answered.
Mean score= Sum of the items over the number of 
it
d
If more than 50% of the items in the scale are
missing, the scale scores should not be computed,
x
Step 2: Calculate Scores by Dimensions
If
th
50%
f th
it
i
th
x
100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0.
St
2 C l
l t
S
b
Di
i
Items are reversed scored and linearly transformed to a 0-
100
l
f ll
0 100 1 75 2 50 3 25 4 0
Step 1: Transform Score
It
d
d
Weighting of 
Items
Extension of the 
Scoring Scale
Scoring Procedure
Scores are transformed on a scale from 0 to 100.
the Child Report for Young Children (ages 5-7)
No 
3-point scale: 0 (Not at all), 2 (Sometimes) and 4 (A lot) for 
th
Child R
t f
Y
Child
(
5 7)
5-point Likert scale from 0 (Never) to 4 (Almost always)
3
i t
l
0 (N t
t
ll) 2 (S
ti
)
d 4 (A l t)
Item Scaling
Fatigue
Fatigue
Sleep/Rest
Fatigue
Cognitive
F ti
General 
F ti
1-6
1-6
6
Higher scores indicate
lower problems.
1-6 
1-6 
6 
1-6 
Reversed
Scoring
1 6
1-6 
Cluster of 
Items
1 6
6 
Number of 
Items 
6
Direction of 
Dimensions 
Dimensions


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FAMILY IMPACT MODULE SCORING OF DIMENSIONS:
 
 
Emotional 
Functioning
 
5 
1-5  
1-5  
 
 
 
 
Social
4 
1-4  
1-4  
Functioning  
 
 
 
Cognitive  
5  
1-5  
1-5  
Functioning  
 
 
 
 
Communication  
3 
1-3  
1-3  
 
 
 
Worry
5 
1-5  
1-5  
 
 
 
Daily  
3 
1-3  
1-3  
Activities  
 
 
 
Family
5  
1-5  
1-5  
Relationships  
 
 
 
 
 
 
 
Item Scaling
 
5-point Likert scale from 0 (Never) to 4 (Almost always)
 
Weighting of 
Items 
 
No 
 
Extension of the 
Scoring Scale 
 
Scores are transformed to a 0 to 100 scale. 
 
Scoring Procedure  
Step 1: Transform Score 
Items are reversed scored and linearly transformed to a 0- 
100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0 
Step 2: Calculate Scores by Dimensions 
x 
If more than 50% of the items in the scale are 
missing, the scale scores should not be computed, 
x 
Mean score = Sum of the items over the number of 
items answered. 
 
Step 3: Total Scores 
x 
The Total Score is the sum of all 36 items divided by 
the number of items answered 
x 
The Parent HRQL Summary Score (20 items) is 
computed as the sum of the items divided by the 
number of items answered in the Physical, 
Emotional, Social, and Cognitive Functioning scales.
x 
The Family Functioning Summary Score (8 items) is 
computed as the sum of the items divided by the 
 
The Family Functioning Summary Score (8 items) is
computed as the sum of the items divided by the
number of items answered in the Physical,
Emotional, Social, and Cognitive Functioning scales.
Th
F
il F
ti
i
S
S
(8 it
) i
computed as the sum of the items divided by the
b
f i
d i
h
Ph
i
l
the number of items answered
The Parent HRQL Summary Score (20 items) is
t d
th
f th
it
di id d b th
The Total Score is the sum of all 36 items divided by
th
b
f it
d
x
Step 3: Total Scores 
x
x
items answered. 
Mean score = Sum of the items over the number of 
it
d
If more than 50% of the items in the scale are
missing, the scale scores should not be computed,
x
Step 2: Calculate Scores by Dimensions
x
100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0
St
2 C l
l t
S
b
Di
i
Items are reversed scored and linearly transformed to a 0-
y
Step 1: Transform Score
p
It
d
d
Item Scaling
Weighting of 
Items
Extension of the 
Scoring Scale
Scoring Procedure
Scores are transformed to a 0 to 100 scale.
5-point Likert scale from 0 (Never) to 4 (Almost always)
No 
3
5
3
4
5


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number of items answered in the Daily Activities and  
family Relationships scales. 
Interpretation and  
If more than 50% of the items in the scale are missing,  
Analysis  
the Scale Scores should not be computed.  
of Missing Data  
If 50% or more items are completed: Impute the mean of  
 
the completed items in a scale.  
 
 
4.1.7 ABC-Irritability Subscale (ABC-I) 
The ABC-I will be used to assess suicidality. The entire ABC-C will be administered 
although only the ABC-I will be used to assess the potential for self-harm. 
The original calculation method includes 5 subscales with the sub scores derivation as 
follows: 
 
SUBSCALES 
Sum of Questions 
Irritability 
2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, 57 
Lethargy/Social 
Withdrawal 
3, 5, 12, 16, 20, 23, 26, 30, 32, 37, 40, 42, 43, 53, 55, 
58 
Stereotypic Behavior 
6, 11, 17, 27, 35, 45, 49 
 
Hyperactivity 
1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 51, 54, 
56 
Inappropriate speech 
9, 22, 33, 46 
 
For missing data, the following upper limits will apply (number of missing items 
tolerated for each subscale before discarding the data for that subscale): (I) Irritability 
(15-item scale): 3 items; (II) Lethargy/Social Withdrawal (16-item scale): 3 items; 
(III) Stereotypic Behavior (7-item scale)” 2 items; (IV) Hyperactivity/Noncompliance 
(16-item scale): 3 items; (V) Inappropriate Speech (4-item scale): 1 item. If more 
items than the stated upper limit have been left blank, the subscale will not be 
computed. If the subscale has the required minimum number of items, the subscale 
scores will be prorated as follows: (a) Take the total number of items on the subscale 
and divide this by the number of completed items. This will result in a number larger 
than 1.00. (b) Multiply that number by the total score for that subscale. (c) This 
becomes the new total score for this subscale for the given subject. 
There is no total score for adding all the subscales together. 


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4.1.8 Vital Sign Reference Ranges 
Reference ranges of vital signs by age group are described in the following table from 
The Harriet Lane Handbook: A manual for Pediatric House Officers, Twentieth 
Edition, 2015. A value on the boundary is considered normal; therefore, using the 
systolic blood pressure example for 2 to 3 years, a value of 105 mmHg would be 
considered normal, and a value of 106 mmHg abnormal. 
 
 
4.2 Computation of Derived Data 
4.2.1 Time Points and Duration 
Standard calculations used across many assessments: 
 Changes from baseline = Post Baseline value – Baseline value 
 Percentage change from baseline = [(Post Baseline value – Baseline 
value)/Baseline Value]*100. 
 
4.2.2 Other Data Derivations 
Body Mass Index BMI = Weight in Kg / (Height in meter)2 


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5 PROGRAMMING SPECIFICATIONS 
5.1 Analysis Specifications 
Sample SAS code for the MMRM ANCOVA analysis is as follows: 
proc mixed data=temp method=reml; 
class subject visit treat agegrp region; 
model endpoint = visit treat agegrp region baseline 
visit*treat ; 
repeated visit / subject=subject type=covstruc; 
lsmeans visit*treat / diff=all cl alpha=0.05; 
run; 
Use the following sequence for choosing a covariance structure, covstruc. 
Use the first covariance structure that converges: 
 
 
 
 
 
 
 
 
 
 
 
 
If the model converges with an unstructured covariance matrix, the Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom. If a 
structured covariance is used for the model, then a robust sandwich estimator will be 
utilized for estimating the variance of the treatment effect estimate. 
For the MMRM ANOVA model, baseline is excluded from the model statement. 
Sample SAS code for the generalized logit model analysis is as follows: 
PROC GLIMMIX DATA = xxx; 
CLASS subject visit treat agegrp region; 
MODEL endpoint = visit treat agegrp region visit*treat / 
DIST= b link=logit; 
random intercept / subject=subject type = covstruc; 
LSMEANS visit*treat / diff exp cl or; 
RUN; 
SAS Name for Covariance 
Structure 
Covariance Description 
UN 
Unstructured 
TOEPH 
Heterogeneous Toeplitz 
ARH(1) 
Heterogeneous Autoregressive(1) 
CSH 
Heterogeneous Compound Symmetry 
TOEP 
Toeplitz 
AR(1) 
Autoregressive(1) 
CS 
Compound Symmetry 


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Use the sequence for choosing a covariance structure, covstruc, described above with 
the unstructured covariance replaced by an unstructured Cholesky covariance. 
Sample SAS code for the logistic analysis is as follows: 
PROC LOGISTIC DATA = xxx; 
CLASS treat agegrp region; 
MODEL endpoint = treat agegrp region; 
LSMEANS treat / diff cl or; 
RUN; 
 
 
5.2 General Specifications 
It is suggested that computer-generated table output adhere to the following 
specifications. 
1. Unless otherwise specified, all computer-generated tables and listings should be 
produced in landscape mode using SAS ODS to create RTF output which can be 
imported by Microsoft Word in table format. All output should have the 
following two-line header at the upper left margin: 
Ovid Therapeutics Inc. 
OV101-19-001 
and the following header at the upper right margin: 
Page x of y 
2. Each table should be identified by in a sequential numeric order, and the table 
designation should be centered above the title. A decimal system within the 
numeric numbering (i.e., x.y and x.y.z) should be used to identify tables, listings 
and figures with related contents. The title is centered in initial capital characters 
and should include the analysis set analyzed (e.g. SS). The title and table 
designation are single-spaced, but are separated from the table by at least a double 
space. 
Table No. 
 
First Line of Title 
Second Line of Title (if needed) 
Analysis Set Analyzed 
 
3. Column headings should be in proper case. 
4. For variables with numeric values, include “unit” in column heading when 
appropriate. 
5. Footnotes should be single spaced, but separated by at least a double space from 
the bottom line of the table. The notes are aligned vertically by the left vertical 


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border of the table. All output should have at least the footnote about the program 
name and date of the program run. 
[1] Footnote 1 
[2] Footnote 2 
[3] Footnote 3 
PROGRAM: program file name 
DDMMMYYYY HH:MM 
6. Unless specified otherwise, all data listings should be sorted by subject number 
with the study center, and by visit date within subject, where appropriate. 
7. For tables that summarize categorical (discrete) data, a Missing category should 
be added to any parameters for which information is not available for any subject. 
8. Unless otherwise specified, the estimated mean, median, first and third quartiles 
(Q1 and Q3, respectively) for a set of values should be printed out to one more 
decimal place than the raw (observed) data and rounded appropriately. Standard 
errors (or standard deviations) should be printed out to two additional decimal 
places than the raw (observed) data and rounded appropriately. For example, for 
age (with raw data in whole years): 
n 
xx 
Mean (SD) 
xx.x (xx.xx) 
Median 
 
xx.x 
Q1, Q3 
xx.x, xx.x 
Min, Max 
xx, xx 
 
9. The p-values will be printed in the tables rounded appropriately to 4 decimal 
places and formatted as '0.xxxx'. P-values less than 0.0001 will be formatted in 
the tables as '<0.0001'. 
10. All fractional numeric values should be printed with a zero to the left of the 
decimal point (e.g., 0.12, 0.3). 
11. Unless otherwise specified, percentage values should be printed with one digit to 
the right of the decimal point (e.g., 12.8, 5.4). 
12. Missing descriptive statistics due to non-estimability in tables, as well as missing 
data in subject listings should be represented as either a hyphen (“-“) with a 
corresponding footnote (“ - = unknown or not evaluated”), or as “N/A” with the 
footnote “N/A = not applicable” whichever is appropriate. 
13. Dates printed as a result in the table, listing, or graph should be printed in SAS 
DATE9. format (“DDMONYYYY”: 01 JUL 2002). Missing portions of dates 
should be represented on subject listings as dashes (-- JUL 1999). Dates that are 
missing because they are not applicable for the subject should be listed as “N/A”, 
unless otherwise specified. 


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23(8):1043-51.
psychometric properties of a survey instrument for school-aged children. Sleep. 2000;
Owens J, Spirito A, McGuinn M. The Children's Sleep Habits Questionnaire (CSHQ): 
Child Neurol. 2005; 47:592-7.
and adolescents with cerebral palsy: hearing the voices of the children. Develop Med
Varni JW, Burwinkle TM, Sherman SA, et al. Health-related quality of life of children
Module: preliminary reliability and validity. Health Qual Life Outcomes. 2004; 2:55.
Varni JW, Sherman SA, Burwinkle TM, et al. The PedQoLI™ Family Impact
 
 
6 REFERENCES 
Aman MG, Singh NN, Stewart AW, Field CJ. The Aberrant Behavior Checklist: A 
behavior rating scale for the assessment of treatment effects. American Journal of 
Mental Deficiency. 1985;89(5):485–491. 
ICH E9 Guideline: Statistical Principles for Clinical Trials, 5 February 1998. 
ICH-E9 (R1) Guideline: Addendum: Estimands and Sensitivity Analysis in Clinical 
Trials, 16 June 2017. 
Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not 
affect the type I error rate. Statistics in Medicine 2003; 22:3571-3581. 
Ouyang J, Carroll KJ, Koch G, Li J. Coping with missing data in phase III pivotal 
registration trials: Tolvaptan in subjects with kidney disease, a case study. 
Pharmaceutical Statistics. 2017; 16: 250–266. 
 
Sparrow, S. S., D. V. Cicchetti and D. A. Balla (2005). Vineland II: Vineland Adaptive 
Behavior Scales. Circle Pines, MN, American Guidance Service. 
Sparrow, S. S., D. V. Cicchetti and C. A. Saulnier (2016). Vineland Adaptive Behavior 
Scales, third edition (Vineland-3). Circle Pines, MN, American Guidance Service.