Conditions: Fragile X Syndrome (FXS)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

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

Detailed description:

Arms:
arm 1: Once Daily arm 2: Twice Daily arm 3: Three Times Daily

Interventions: intervention 1: OV101 (gaboxadol)
Intervention descriptions: intervention 1: OV101 (gaboxadol)

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
A Phase 2a, Randomized, Double-Blind, Parallel-Group, Proof-of-Concept 
Study Evaluating the Safety, Tolerability, and Efficacy of OV101 in 
Fragile X Syndrome 
PROTOCOL NUMBER OV101-17-001 
 
Sponsor: 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
Sponsor Contact: 
Amit, MD, MBA 
Chief Medical Officer and Head of R&D 
arakhit@ovidrx.com 
Telephone: 646-661-1548 
 
Safety Monitor: 
 
Ovid/Sciformix 
Safety Hotline: 1-800-403-6981 
Safety Fax Line: 1-800-403-6981 
Medical Monitor: 
Eric J Christopher, MD, FAPA 
Associate Medical Director 
PPD 
Eric.Christopher@ppdi.com 
Version of Protocol: 
1.2 (Protocol Amendment 2)  
Date of Protocol: 
27 Mar 2019 
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. 
 


 


Ovid Therapeutics Inc. 
Protocol: OV101-17-001 Version 1.2 
27 Mar 2019 
 
Declaration of Investigator 
I have read and understood all sections of the protocol titled “A Phase 2a, Randomized, 
Double-Blind, Parallel-Group, Proof-of-Concept Study Evaluating the Safety, Tolerability, 
and Efficacy of OV101 in Fragile X Syndrome” and the accompanying investigator’s 
brochure. 
 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with Final Protocol Version 1.21, dated 27 Mar 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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Protocol Amendment #2 Summary of Changes ......................................................................... 6 
Table of Contents 
 
 
Table of Contents ..................................................................................................................... 14 
List of Tables ............................................................................................................................ 19 
List of Figures .......................................................................................................................... 19 
Protocol Synopsis ..................................................................................................................... 20 
List of Abbreviations ................................................................................................................. 28 
1 
Introduction ....................................................................................................................... 30 
1.1 
Background on Fragile X Syndrome (FXS) ............................................................ 30 
1.2 
Clinical Manifestation of FXS ................................................................................ 31 
1.3 
Background on OV101 ........................................................................................... 32 
1.4 
Clinical Experience with OV101 ............................................................................ 34 
1.5 
Pharmacokinetics in adults and adolescents ............................................................ 35 
1.6 
Study Rationale and the Role of GABA in FXS ..................................................... 36 
2 
Study Objectives ............................................................................................................... 38 
2.1 
Primary Objectives .................................................................................................. 38 
2.2 
Secondary Objectives .............................................................................................. 38 
2.3 
Exploratory Objectives ............................................................................................ 38 
3 
Investigational Plan .......................................................................................................... 39 
3.1 
Study Design ........................................................................................................... 39 
3.1.1 
Rationale of Dose Selection ..................................................................... 41 
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 .................................................................................... 43 
4.2 
Discontinuation of Subjects From Study Treatment and the Study ........................ 44 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................. 44 
4.2.2 
Handling of Withdrawals ......................................................................... 45 
4.2.3 
Replacements ........................................................................................... 46 


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5 
Study Treatments .............................................................................................................. 47 
5.1 
Method of Assigning Subjects to Treatment Groups .............................................. 47 
5.2 
Treatments Administered .......................................................................................... 47 
5.3 
Description of Study Drug ...................................................................................... 47 
5.4 
Management of Clinical Supplies ........................................................................... 48 
5.4.1 
Study Drug Packaging and Storage .......................................................... 48 
5.4.2 
Test Article Accountability ......................................................................... 49 
5.4.3 
Other Supplies .......................................................................................... 49 
5.5 
Overdose Management ............................................................................................. 50 
5.5.1 
Treatment of Overdose ............................................................................. 50 
5.5.2 
Medication Errors .................................................................................... 50 
5.5.3 
Treatment of Medication Errors ............................................................... 50 
5.6 
Blinding ................................................................................................................... 50 
5.6.1 
Breaking the Blind ................................................................................... 50 
5.7 
Treatment Compliance ............................................................................................ 51 
5.8 
Prior and Concomitant Therapy .............................................................................. 51 
5.8.1 
Prohibited Medications and Therapies ..................................................... 52 
5.8.2 
Restrictions ............................................................................................... 52 
6 
Study Assessments and Procedures .................................................................................. 53 
6.1 
Study Visits ............................................................................................................. 57 
6.1.1 
Screening Period ....................................................................................... 57 
6.1.2 
Baseline Visit ........................................................................................... 58 
6.1.2.1 Management of Sleep Diary and Actigraph ............................................. 59 
6.1.3 
Phone Visits to Assess Safety ................................................................... 60 
6.1.4 
Week 2 Clinic Visit .................................................................................. 60 
6.1.4.1 Management of Sleep Diary and Actigraph ............................................. 61 
6.1.5 
Week 6 Clinic Visit .................................................................................. 62 
6.1.5.1 Management of Sleep Diary and Actigraph ............................................. 63 
6.1.6 
End-of-Treatment Visit ............................................................................ 63 
6.1.6.1 Management of Sleep Diary and Actigraph ............................................. 64 
6.1.7 
End-of-Study Visit ................................................................................... 65 
6.1.7.1 Management of Sleep Diary and Actigraph ............................................. 65 
6.2 
Screening Assessments ............................................................................................ 66 


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6.4.1  
Metabolomic Biomarkers .......................................................................... 73 
6.4.2 
Cheek Microbiome Assessments .............................................................. 73 
Plasma OV101 Concentrations ................................................................................ 73 
6.3.3.4 
Event Related Potential ............................................................................ 72 
6.4 
Exploratory Laboratory Assessments ...................................................................... 73 
6.5 
6.2.1 
Autism Spectrum Disorder ....................................................................... 66 
6.2.2 
Intelligence Quotient ................................................................................ 66 
6.3 
Efficacy Assessments ............................................................................................... 66 
6.3.1 
Caregiver Assessments ............................................................................. 67 
6.3.1.1 Aberrant Behavior Checklist-Community ............................................... 67 
6.3.1.2 Anxiety, Depression, and Mood Scales .................................................... 68 
6.3.1.3 Repetitive Behavior Scale-Revised .......................................................... 68 
6.3.1.4 Conners 3rd Edition .................................................................................. 68 
6.3.1.5 Short Sensory Profile-2 ............................................................................ 68 
6.3.1.6 Children’s Sleep Habits Questionnaire .................................................... 68 
6.3.1.7 Sleep Diary ............................................................................................... 69 
6.3.1.8 Behavior Assessment System for Children, 3rd Edition ........................... 69 
6.3.1.9 Parent Global Impressions Scales ............................................................ 69 
6.3.1.10 Pediatric Quality of Life Inventory .......................................................... 70 
6.3.2 
Clinician Assessments .............................................................................. 70 
6.3.2.1 Structured Sleep History Form ................................................................. 70 
6.3.2.2 Pediatric Sleep Clinical Global Impressions Scales ................................. 70 
6.3.2.3 Caregiver Top 3 Concerns Visual Analog Scale ....................................... 70 
6.3.2.4 Vineland Adaptive Behavior Scale ........................................................... 71 
6.3.2.5 Clinical Global Impressions Scales .......................................................... 71 
6.3.3 
Direct Subject Assessments ...................................................................... 71 
6.3.3.1 Actigraphy ................................................................................................ 71 
6.3.3.2 Test of Attentional Performance for Children .......................................... 72 
6.3.3.3 Repeatable Battery for the Assessment of Neuropsychological Status .... 72 
 
 
 
6.6 
Safety and Tolerability Assessments ....................................................................... 74 
6.6.1 
Adverse Events ......................................................................................... 74 
6.6.1.1 Definitions of Adverse Events .................................................................. 74 
6.6.1.2 Serious Adverse Events ............................................................................ 74 
6.6.1.3 Eliciting and Documenting Adverse Events ............................................. 75 


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6.6.1.4 Reporting Adverse Events ........................................................................ 75 
6.6.1.5 Reporting Serious Adverse Events ........................................................... 76 
6.6.1.6 Suspected Unexpected Serious Adverse Reactions .................................. 77 
6.6.1.7 Assessment of Severity ............................................................................ 78 
6.6.1.8 Assessment of Causality ........................................................................... 78 
6.6.1.9 Follow-up of Subjects Reporting Adverse Events ................................... 79 
6.6.2 
Other Safety Assessments ......................................................................... 79 
6.6.2.1 Vital Sign Measurements ......................................................................... 79 
6.7 
Monitoring Committees .......................................................................................... 79 
6.7.1 
Internal Monitoring Committee ................................................................ 80 
6.7.2 
Scientific Oversight Committee ............................................................... 80 
6.8 
Clinical Assessment of Suicidality .......................................................................... 80 
6.9 
Laboratory Analyses ................................................................................................ 80 
6.10 Sample Collections .................................................................................................. 81 
7 
Statistical and Analytical Plan .......................................................................................... 83 
7.1 
Primary Safety Endpoints ........................................................................................ 83 
7.2 
Secondary Efficacy Endpoints ................................................................................ 83 
7.3 
Exploratory Efficacy Endpoints .............................................................................. 83 
7.3.1 
Caregiver-Completed Endpoints .............................................................. 83 
7.3.2 
Clinician-Completed Endpoints ............................................................... 83 
7.3.3 
Direct Subject Assessment Endpoints ...................................................... 84 
7.5 
Sample Size Calculations ......................................................................................... 84 
7.6 
Analysis Sets ........................................................................................................... 85 
7.7 
Description of Subgroups to be Analyzed ............................................................... 86 
7.8 
Statistical Analysis Methodology ............................................................................ 86 
7.8.1 
Safety Analyses ........................................................................................ 87 
7.8.2 
Analysis of Secondary Efficacy Endpoints .............................................. 88 
7.8.3 
Analyses of Exploratory Endpoints ......................................................... 88 
7.8.5 
Exploratory Modelling ............................................................................. 89 
7.8.6 
Other Analyses ......................................................................................... 89 
7.8.6.1 Demographics and Other Baseline Characteristics .................................. 89 
Analyses of Other Exploratory Endpoints ............................................... 88 
7.8.4 
Other Exploratory Endpoints ................................................................................... 84 
7.4 


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7.8.6.2 Drug Treatments ....................................................................................... 90 
7.8.7 
Interim Analyses....................................................................................... 90 
8 
Data Quality Assurance .................................................................................................... 91 
8.1 
Data Management ..................................................................................................... 91 
9 
Ethics ................................................................................................................................ 93 
9.1 
Institutional Review Board(s) ................................................................................. 93 
9.2 
Ethical Conduct of the Study .................................................................................. 93 
9.3 
Subject Information and Consent ............................................................................ 93 
10 Investigator’s Obligations ................................................................................................. 95 
10.1 Confidentiality ......................................................................................................... 95 
10.2 Financial Disclosure and Obligations ...................................................................... 95 
10.3 Investigator Documentation .................................................................................... 96 
10.4 Study Conduct ......................................................................................................... 96 
10.5 Adherence to Protocol ............................................................................................. 96 
10.6 Adverse Events and Study Report Requirements .................................................... 97 
10.7 Investigator’s Final Report ...................................................................................... 97 
10.8 Records Retention .................................................................................................... 97 
10.9 Publications ............................................................................................................. 97 
11 Study Management ........................................................................................................... 98 
11.1 Monitoring ............................................................................................................... 98 
11.1.1 
External Data Monitoring Committee ...................................................... 98 
11.1.2 
Monitoring of the Study ........................................................................... 98 
11.1.3 
Inspection of Records ............................................................................... 98 
11.2 Management of Protocol Amendments and Deviations .......................................... 99 
11.2.1 
Modification of the Protocol ..................................................................... 99 
11.2.2 
Protocol Deviations .................................................................................. 99 
11.3 Study Termination ................................................................................................... 99 
11.4 Final Report ............................................................................................................ 100 
12 Reference List .................................................................................................................. 101 
13 Appendix (Israel Site-Specific Instructions) .................................................................... 105 


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Table 5-1 
Pharmaceutical Composition of OV101 for the 5-mg Capsule ........................ 48 
List of Tables 
 
 
Table 5-2 
Treatment Group Regimens ............................................................................ 49 
 
Table 6-1 
Schedule of Activities by Clinic Visit ............................................................. 54 
 
Table 6-2 
Efficacy Assessments by Domain and Participant Source .............................. 67 
 
Table 7-1 
Incidence Rates and Corresponding Precision ................................................ 85 
 
List of Figures 
Figure 1–1 
Main Sites of Action of OV101, Benzodiazepine, and Novel Benzodiazepine- 
Like Compounds ............................................................................................. 33 
 
Figure 3–1 
Study Schematic .............................................................................................. 39 


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Protocol Synopsis 
 
Protocol Number: 
OV101-17-001 
Title: 
A Phase 2a Randomized, Double-Blind, Parallel Group, Proof-of-Concept Study Evaluating 
the Safety, Tolerability, and Efficacy of OV101 in Fragile X Syndrome 
Sponsor: 
Ovid Therapeutics Inc. 
1460 Broadway 
New York, NY 10036 
Study Phase: 
Phase 2a 
Study Sites: 
Approximately 8 sites in the United States and approximately 1 site in Israel 
Indication: 
Fragile X syndrome 
Rationale: 
Ovid Therapeutics Inc. is developing OV101 (gaboxadol) for the treatment of rare genetic 
disorders that are associated with severe developmental and behavioral challenges, such as 
Angelman syndrome and Fragile X syndrome (FXS). Gaboxadol was initially developed for 
the treatment of insomnia by H. Lundbeck A/S and Merck, but its development was 
discontinued in 2007 for clinical and commercial reasons. Extensive nonclinical and clinical 
data were generated during the initial stages of development, including data from exposure to 
gaboxadol in more than 4300 adult subjects with insomnia and approximately 500 adult 
subjects in non–insomnia-related studies. 
Fragile X syndrome is the most common inherited form of intellectual disability, with a 
prevalence of 1 in 4000 males and 1 in 8000 females. It is also the most common known 
genetic cause of autism; approximately 25% to 30% of individuals with FXS meet the full 
diagnostic criteria for autism, and approximately 5% of children with autism carry the fragile 
X mutation. Males with FXS have moderate to severe intellectual disability, and females with 
FXS range from normal to moderate impairment. 
Individuals with FXS are at increased risk for a range of behavioral problems that may limit 
their academic performance, adaptive function, daily living skills, and social interactions. 
Anxiety is the most common behavioral problem in individuals with FXS, with specific 
symptoms of shyness, social anxiety, hyperarousal, and stereotypic behavior such as hand 
flapping and hand biting. Aggressive behaviors in male individuals with FXS are also 
common and may lead to injuries to caregivers, peers, or friends. Attention- 
deficit/hyperactivity disorder symptoms (overarousal, hyperactivity, distractibility, and 


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impulsivity) may also be noted. Individuals with FXS can experience problems in one or 
more of these behavior domains. There is a wide range of variability in symptoms, although 
they tend to be more severe in males than in females. 
Current behavior therapy treatments include speech therapy, physical therapy, occupational 
therapy, and educational resources. Current treatments with medications target only the 
behavioral phenotypes and not 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. The mechanism of action of OV101 is unique among 
GABAergic agents, including benzodiazepines, zolpidem and other zolpidem-like drugs, 
neurosteroids, and drugs that act on GABA metabolism or uptake. 
The use of OV101 for treatment of individuals with FXS is based on studies in a relevant 
mouse model of the disease, the Fmr1 knockout (KO) mouse, which lacks the fragile X 
mental retardation protein due to a disruption in its FMR1 gene. Fmr1 KO mice have 
decreased GABA synthesis, decreased presynaptic GABA release, and decreased 
extrasynaptic levels of GABA, resulting in decreased tonic inhibition. OV101 was shown to 
restore tonic inhibition in the amygdala, reduce sensory hypersensitivity and motor 
hyperactivity, and improve pre-pulse inhibition (signal to noise ratio) in Fmr1 KO mice. 
Cogram et al recently presented data that showed full normalization of abnormal repetitive, 
social, and anxiety-like behaviors with OV101 in another FXS KO mouse model, the Fmr1 
KO2 mouse. Taken together, these data support the potential of OV101 to treat the core 
behavioral deficits noted in individuals with FXS. Importantly, the ability of OV101 to 
potentiate tonic inhibition is unlike any other GABAergic agent, including benzodiazepines, 
zolpidem, other zolpidem-like drugs, neurosteroids, and drugs that act on GABA metabolism 
or uptake. 
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. 
The purpose of this study is to investigate the safety, tolerability, and exploratory efficacy of 
treatment by oral administration of OV101 at doses of 5 mg/day (5 mg once a day [QD]), 
10 mg/day (5 mg twice a day [BID]), or 15 mg/day (5 mg three times a day [TID]) in 
adolescent and adult male subjects with FXS. The 12-week, randomized, double-blind, 
parallel-group, proof-of-concept study design will inform OV101 clinical development and 
the design of future studies in FXS. 


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Objectives: 
Primary Objectives: 
 To evaluate the safety and tolerability of OV101 over 12 weeks of treatment across 
different daily dosing regimens in adolescent and adult male subjects with FXS 
Secondary Objectives: 
 To evaluate changes in behavior during 12 weeks of treatment with OV101 across 
different daily dosing regimens in adolescent and adult male subjects with FXS 
Exploratory Objectives: 
 To evaluate changes in sleep, adaptive functioning, and quality of life across different 
daily dosing regimens of OV101 treatment over 12 weeks in adolescent and adult 
male subjects with FXS 
 To evaluate possible acute rebound phenomena (eg, sleep disruption or behavioral 
problems) that occur following discontinuation of treatment with OV101 using 
outcome assessments administered at a follow-up visit 4 to 6 weeks after the end of 
treatment 
 To explore the relationships among plasma levels of OV101, metabolomic 
biomarkers, and treatment response 
 To explore the relationships among subjects’ microbiomes and clinical presentation of 
FXS or treatment response 
 To explore the relationships between event related potential measurements and levels 
of OV101 or treatment response 
 To explore the relationships among study endpoints (eg, behavior, sleep), where 
appropriate 
 To obtain plasma OV101 concentrations for use in combination with data from other 
studies to perform population PK and PK-pharmacodynamic (PD) analysis and to 
evaluate the exposure-response of OV101 in individuals with FXS 
Study Population: 
Inclusion criteria: 
1. Is male and 13 to 22 years old (inclusive) at the time of informed consent.  
2. Has a diagnosis of FXS with a confirmed FMR1 full mutation (≥200 CGG repeats). 
The diagnosis must be confirmed by genetic testing prior to subject randomization. 
3. Has a Clinical Global Impression-Severity score of 4 (moderately ill) or greater at 
screening. 
4. Is currently being treated with no more than 3 anti-epileptic and/or psychoactive 
medications, including those prescribed off-label to address behavioral conditions. 
Any concomitant medication, including anti-epileptic and/or behavioral medications, 
supplements, and special diets, must be at a stable dose for at least 4 weeks before 
randomization and must be maintained at that dose throughout the duration of the 
study. 


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5. Has a legally acceptable representative (LAR)/caregiver capable of providing 
informed consent and able to attend all scheduled study visits, oversee the 
administration of study drug, and provide feedback regarding the subject’s behavior 
and other symptoms as described in the protocol. 
6. Provide assent to the protocol (to the extent possible and in accordance with local 
institutional review board and regulatory requirements) and have an LAR/caregiver 
who will provide written informed consent. Subjects providing assent must do so at 
the same visit as LAR/caregiver written informed consent is provided. 
7. Is able to attend all scheduled study visits and willing and capable of performing the 
required study assessments. 
8. Is able to ingest the study drug capsules (including sprinkling capsule contents onto 
1 spoon of applesauce or low-fat yogurt). 
9. Has an intelligence quotient less than 75 as measured by the Stanford-Binet-5 at 
screening or a previously documented SB-5 measurement conducted within 6 months 
of the screening visit. For the site in Israel, please see Appendix for site-specific 
details regarding the IQ test. 
10. Will agree to remain sexually abstinent from the first day of screening until 30 days 
after the last dose of study treatment. 
11. Has LAR/caregivers who will agree not to post any of the subject’s personal medical 
data related to the study or information related to the study on any website or social 
media site (eg, Facebook and Twitter) until they have been notified that the study is 
completed. 
Exclusion criteria: 
1. Has a concomitant disease (eg, gastrointestinal, renal, hepatic, endocrine, respiratory, 
or cardiovascular system disease) or 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 this study. 
2. Has clinically significant lab abnormalities or vital signs at the time of screening (eg, 
alanine aminotransferase or aspartate aminotransferase >2.5 × upper limit of normal; 
total bilirubin or creatinine >1.5 × upper limit of normal). Re-testing of safety labs 
may be allowed after consultation with the medical monitor or designee. 
3. Uses any GABAergic agent (eg, acamprosate, baclofen, vigabatrin, tiagabine, 
riluzole, benzodiazepines, and gabapentin) when used on a regular schedule. 
Benzodiazepines administered for situational anxiety (eg, for occasional procedures 
or events) are permitted. 
4. Uses any cannabinoid derivatives. 
5. Has a history of uncontrollable seizure disorder or seizure episodes within 6 months 
of screening or change in the anticonvulsant pharmacotherapy in the past 3 months. 
6. Has a history of suicidal behavior or considered by the investigator to be at high risk 
of suicide. 
7. Has any condition or there is any reason that, in the opinion of the investigator, makes 


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the subject unsuitable for enrollment 
8. Is unable or does not have an LAR/caregiver able to comply with study requirements. 
9. Has enrolled in any clinical trial or used of any investigational agent, device, and/or 
investigational procedure within the 30 days before screening or does so concurrently 
with this study. 
10. Is a family member of the investigator or study site personnel. 
Study Design: 
This is a Phase 2a, randomized, double-blind, parallel-group study to evaluate the safety, 
tolerability, and efficacy of OV101 at 3 daily doses: 5 mg/day (5 mg QD), 10 mg/day (5 mg 
BID), and 15 mg/day (5 mg TID) in adolescent and adult male subjects with FXS. Subjects 
with a clinically and molecularly confirmed diagnosis of FXS will be eligible for inclusion in 
the study. The study will comprise a screening period of at least 1 week (to allow for 
actigraphs) and up to 3 weeks; a baseline visit on Day 1 for treatment randomization 
(enrollment), baseline assessments, and first dose of study drug; clinic visits for safety and 
efficacy assessments over a 12-week treatment period, including clinic visits at Week 2, 
Week 6, and Week 12 (end-of-treatment [EOT]); and an end-of-study (EOS) follow-up visit 
occurring any time between the ends of Week 16 and Week 18. 
For each subject, after informed consent is obtained, screening assessments will be 
completed within the 3 weeks preceding Baseline. At Baseline, subjects 13 to 22 years old 
(inclusive) who meet all eligibility criteria will be enrolled on Day 1 in a 1:1 target ratio 
between adolescents (13 to17 years old, inclusive) and adults (18 to 22 years old, inclusive). 
A sufficient number of subjects will be enrolled to ensure that at least 30 evaluable subjects 
complete 12 weeks of treatment. 
Subjects will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups (5 mg QD, 5 
mg BID, and 5 mg TID), stratified by age group (adolescent/adult) to achieve balance among 
treatment arms. All subjects will take study drug TID (morning, afternoon, and evening), 
OV101 in the morning and OV101 or placebo in the afternoon and evening throughout the 
treatment period (including Baseline). There will not be any dose adjustments permitted 
during the study. 
After random assignment at Baseline, subjects will receive the assigned package of blinded 
study treatment according to the treatment code for the first 6 weeks of treatment and will 
take their first dose of study drug at the clinic. They will receive another assigned package of 
study treatment at the Week 6 clinic visit. 
Subjects (assisted by LAR/caregivers) will complete paper sleep diaries and wear actigraphs 
over the 7-day periods immediately preceding Baseline and the Week 2, Week 6, EOT, and 
EOS clinic visits. The Baseline, Week 2, Week 6, and EOT visits will be full-day clinic visits. 
Safety information will be collected during phone calls at the end of Weeks 1, 4, 8, and 10 
(on Days 8, 29, 57, and 71, respectively), in addition to during every clinic visit (screening, 
Day 1, Week 2, Week 6, EOT, and EOS). At the investigator’s discretion, subjects may be 
evaluated at unscheduled clinic visits for reasons related to subject safety. At unscheduled 
visits, subjects will be queried about AEs, changes in concomitant medications, and 


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suicidality, and safety laboratory assessments may be conducted. Periodic interim blinded 
review of safety data will be performed as part of routine pharmacovigilance activities. 
Estimated Study Duration: 
After informed consent is obtained, screening assessments will be conducted within the 
3 weeks preceding Baseline, followed immediately by treatment for 12 weeks and a 4- to 
6-week follow-up period, for a maximum duration of individual subject participation of 
21 weeks. 
Efficacy Assessments: 
Efficacy assessments will include the Aberrant Behavior Checklist–Community; the Anxiety, 
Depression, and Mood Scales; the Repetitive Behavior Scale–Revised; the Conners3rd 
Edition; the Short Sensory Profile–2; the Pediatric Sleep Clinical Global Impressions 
(Severity and Improvement) scales; Children’s Sleep Habits Questionnaire; a 7-day sleep 
diary; the Behavior Assessment System for Children, 3rd Edition Parenting Relationship 
Questionnaire; Parent Global Impressions (Severity and Improvement) scales; the Pediatric 
Quality of Life Inventory; a top 3 concerns visual analog scale; the Vineland Adaptive 
Behavior Scale–3rd Edition; Clinical Global Impressions (Severity and Improvement) scales; 
7-day actigraphy; a computerized measurement of cognition using the Test of Attentional 
Performance for Children; the Repeatable Battery for the Assessment of Neuropsychological 
Status; and an optional event related potential. 
Pharmacokinetic Assessments: 
Blood samples will be collected for the determination of plasma OV101 concentrations at 
Baseline and Weeks 2, 6, and EOT at the following time points: 
 One PK sample collected between 0.5 and 0.75 hours postdose 
 One PK sample collected between 3 and 4 hours postdose 
Plasma OV101 concentration data obtained from this study may be combined with data from 
prior studies to perform population PK and PK-PD analyses and to evaluate the exposure- 
response of OV101 in individuals with FXS. The results of these analyses will be reported 
separately from the clinical study report for this study. 
Safety Assessments: 
All subjects who receive study drug will be evaluated for study drug safety and tolerability. 
Assessments will include: frequency and severity of treatment-emergent adverse events 
(TEAEs) and serious adverse events (including TEAEs leading to discontinuation), 
standardized clinical assessment of suicidality, clinical laboratory evaluations, and vital sign 
measurements. 
Study Drug, Dosage, and Route of Administration: 
Subjects will be assigned to receive 1 of 3 daily doses of OV101: 5 mg/day, 10 mg/day, or 
15 mg/day. Subjects will take all doses orally (assisted by an LAR/caregiver, if necessary), 
TID (morning, afternoon, evening) at approximately the same times each day, for the 
duration of the 12-week treatment period. 


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OV101 Treatment Group 
Morning Dose 
Afternoon Dose 
Evening Dose 
5 mg/day 
5-mg OV101 capsule 
Placebo capsule 
Placebo capsule 
10 mg/day 
5-mg OV101 capsule 
Placebo capsule 
5-mg OV101 capsule 
15 mg/day 
5-mg OV101 capsule 
5-mg OV101 capsule 
5-mg OV101 capsule 
The morning and afternoon doses should be taken with food, and the afternoon dose should 
be taken at least 6 hours after the morning dose. The evening dose should be taken 
30 minutes before bedtime. Capsules may be opened and the contents sprinkled onto 
1 teaspoon of low-fat semi-liquid food (eg, 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 specifically how each 
capsule was taken (eg, swallowed whole or taken in 1 teaspoon of food). 
Placebo capsules will be identical in appearance to the capsules containing OV101 and have 
the same excipient ingredients but will not contain OV101. Study drug will be supplied as 
5-mg capsules of OV101 and matching placebo capsules in bottles. Bottles will have 
“Morning,” “Afternoon,” or “Evening” printed on their labels. Each LAR/caregiver will 
receive a 6-week supply of capsules in a package containing 1 “Morning” bottle, 
1 “Afternoon” bottle, and 1 “Evening” bottle at the baseline (Day 1) visit and at the Week 6 
visit. 
Sample Size: 
A sufficient number of subjects (36 estimated) will be enrolled to ensure that 30 evaluable 
subjects complete 12 weeks of treatment. Subjects will be randomly assigned to the 3 OV101 
total daily dosing regimens in a 1:1:1 ratio. 
The main emphasis in reporting the data will be on descriptive statistics and estimation with 
95% CIs. For the objective of estimating the overall subject incidence of TEAEs (for the 
3 OV101 total daily dose arms combined), a true incidence of 20% would be estimated with 
a 13.9% precision (half-width of the 2-sided 95% CI assuming N = 30). 
Analysis Sets: 
The randomized analysis set will be used for summaries of subject disposition, 
demographics, and other baseline characteristics. The safety analysis set (all subjects who 
receive at least 1 dose of study drug) will be used for the analysis of all safety parameters, 
analyzed according to treatment received. The full analysis set (all subjects who receive at 
least 1 dose of study drug and have at least 1 postbaseline efficacy evaluation) will be used 
for analysis of all efficacy parameters, analyzed according to randomized treatment. The 
modified full analysis set may be used for exploratory modelling of selected efficacy 
variables, in addition to the full analysis set. 
Statistical Methods: 
Descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum) will 
be presented for continuous variables and their changes from baseline. In addition, 95% CIs 
for the mean change from baseline will be provided for continuous variables. Graphical 
displays will be utilized to investigate trends over time and dose and the relationship between 


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certain variables and differences between age groups. 
Ordinal variables with sufficient numerical categories (eg, 7-point scales of Parent Global 
Impressions-Severity and Clinical Global Impressions-Severity) and subscale total scores 
from questionnaires will be treated as continuous variables. 
Categorical (not treated as continuous) endpoints (including adverse event incidence and 
binary endpoints) will be summarized by frequency and percentage. Frequencies and 
percentages will be presented for the shifts in these categories (eg, low to normal, low to 
high, high to low) from baseline to each post-treatment assessment time point for scales with 
categorical variables. If there are missing values, the number missing will be presented (as a 
category), but without a percentage. All data collected will be included in by-subject data 
listings. 
All adverse events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and will be classified by MedDRA system organ class (SOC) and preferred term 
(PT). The number and percentage of subjects who experience at least1 TEAE and the number 
and percentage of subjects who experience at least 1 TEAE within each specific SOC and PT 
will be presented by daily dosing regimen and overall. The number of TEAEs (event 
incidence) will also be summarized within each SOC and PT. The Wilson 95% CIs will be 
displayed for the proportion of subjects experiencing TEAEs as a total across the 3 dosing 
regimens. 
Descriptive statistics for efficacy variables at each time point will be displayed by daily 
dosing regimen and overall. Post-hoc exploratory modelling may be conducted on selected 
variables using the full analysis set (and modified full analysis set, as required). 
Individual plasma OV101 concentrations will be listed, plotted, and summarized in the same 
way as other continuous endpoints (number of subjects, mean, SD, median, minimum, and 
maximum). 
Graphical displays (eg, scatter plots of PK concentrations versus PD response) may be 
generated to better understand the OV101 PK-PD profile. 
Version and Date of Protocol: 
Version 1.2, 27 March 2019 


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List of Abbreviations 
 
Abbreviation 
Definition 
ABC-C 
Aberrant Behavior Checklist-Community 
ADAMS 
Anxiety, Depression, and Mood Scales 
AE 
adverse event 
AS 
Angelman syndrome 
BASC-3 PRQ 
Behavior Assessment System for Children, 3rd Edition, Parenting 
Relationship Questionnaire 
BID 
twice a day 
CFR 
Code of Federal Regulations 
CGG 
cytosine-guanine-guanine 
CGI 
Clinical Global Impressions 
CGI-I 
Clinical Global Impressions-Improvement 
CGI-S 
Clinical Global Impressions-Severity 
Conners 3 
Conners 3rd Edition 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
clinical study report 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EEG 
EOS 
electroencephalography 
end of study 
EOT 
end of treatment 
ERP 
event related potential 
FAS 
full-analysis set 
FDA 
US Food and Drug Administration 
FMRP 
fragile X mental retardation protein 
FXS 
fragile X syndrome 
GABA 
gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IQ 
intelligence quotient 


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Abbreviation 
Definition 
IRB 
institutional review board 
IWRS 
interactive web response system 
KABC 
KiTAP 
Kaufman Assessment Battery for Children 
Test of Attentional Performance for Children 
KO 
Knockout 
LAR 
legally acceptable representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified full-analysis set 
MMRM 
Mixed Model with Repeated Measures 
PD 
pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory 
PGI-I 
Parent Global Impressions-Improvement 
PGI-S 
Parent Global Impressions-Severity 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QD 
once a day 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
RBS-R 
Repetitive Behavior Scale-Revised 
SAE 
serious adverse event 
SB-5 
Stanford-Binet-5 
SOC 
system organ class 
SOL 
sleep onset latency 
TEAE 
treatment-emergent adverse event 
TID 
3 times a day 
TST 
total sleep time 
VABS-3 
Vineland Adaptive Behavior Scale, 3rd Edition 
WASO 
WISC 
WPPSI 
wake time after sleep onset 
Wechsler Intelligence Scale for Children 
Wechsler Preschool and Primary Scale of Intelligence 


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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, 
such as Angelman syndrome (AS) and Fragile X syndrome (FXS). Gaboxadol was initially 
developed for the treatment of insomnia by H. Lundbeck A/S and Merck, but its development 
was discontinued in 2007 for clinical and commercial reasons. Extensive nonclinical and 
clinical data were generated during the initial stages of development by Lundbeck/Merck, 
including data from exposure to gaboxadol in more than 4300 adult subjects with insomnia 
and approximately 500 adult subjects in non–insomnia-related studies. Details of the 
Lundbeck/Merck program, including both the nonclinical program and the clinical program, 
are found in the investigator’s brochure (Ovid Therapeutics Inc. 2017). Unless otherwise 
indicated, the source for the information in this introduction is the investigator’s brochure. 
 
1.1 
Background on Fragile X Syndrome (FXS) 
Fragile X syndrome is the most common inherited form of intellectual disability, with a 
prevalence of 1 in 4000 males and 1 in 8000 females (Crawford et al 2001). It is also the 
most common known genetic cause of autism; approximately 25% to 30% of individuals 
with FXS meet the full diagnostic criteria for autism, and approximately 5% of children with 
autism carry the fragile X mutation (Hall et al 2008; Harris et al 2008). Males with FXS have 
moderate to severe intellectual disability, and females with FXS range from normal to 
moderate impairment (Hagerman et al 2010). 
 
The primary molecular basis underlying FXS is a reduced expression level or lack of fragile 
X mental retardation protein (FMRP). Reduced or absent FMRP is most commonly caused 
by an increased number of trinucleotide cytosine-guanine-guanine (CGG) repeats in the 
5’ untranslated region of FMR1 on the X chromosome. The increased number of CGG 
repeats results in hypermethylation of DNA regions where a cytosine nucleotide is followed 
by a guanine nucleotide, which ultimately prevents transcription and leads to either partial or 
full silencing of gene expression. The full mutation, defined as over 200 CGG repeats that 
result in the absence of FMRP, is responsible for the symptoms of FXS. In contrast to the full 
mutation, the premutation (defined as 55 to 200 CGG repeats) leads to enhanced production 
of FMR1 messenger RNA (mRNA; 2 to 8 times the normal levels) (Kenneson et al 2001). 
Enhanced mRNA production can lead to clinical features in premutation carriers that do not 


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occur in individuals with full mutation FXS, including fragile X–associated primary ovarian 
insufficiency and fragile X−associated tremor/ataxia syndrome (Tassone et al 2000). 
 
Understanding the effects of the fragile X mutation on brain development and function has 
been facilitated by genetically engineered animal models that recapitulate the human 
phenotype of FXS. The best established animal model is the Fmr1 knockout (KO) mouse 
(Bakker et al 1994). An RNA-binding protein, FMRP modulates the dendritic localization 
and translation of several hundred mRNA ligands (Fernández et al 2013). In the FMR1 KO 
mouse, the absence of FMRP leads to excessive protein synthesis downstream of signaling 
pathways coupled to group I metabotropic glutamate receptors (mGluRs), in particular 
mGluR5. Inhibition of mGluR5 and downstream signaling has been shown to correct a wide 
array of disease phenotypes in animal models of FXS (Bhakar et al 2012). Glutamatergic 
transmission is under tight regulation by gamma-aminobutyric acid (GABA)-ergic inhibition, 
and deficiencies in GABA-mediated inhibitory neurotransmission have been identified in the 
hippocampus, striatum, somatosensory cortex, and amygdala of Fmr1 KO mice (D’Hulst and 
Kooy 2007). The most consistent neurochemical change in the Fmr1 KO mouse is impaired 
GABAergic neurotransmission, and this dysfunction has been implicated in many of the 
symptoms of FXS, including anxiety, autism-like behavior, epilepsy, and cognitive 
impairment. Specifically, GABAergic tonic inhibition is believed to underlie many of these 
symptoms and may, therefore, be an effective novel target for therapeutic treatment of FXS 
(Gantois et al 2006; Olmos-Serrano et al 2010; Martin et al 2014). Use of GABA agonists 
has been suggested as a therapeutic strategy for FXS (Olmos-Serrano et al 2010; Braat and 
Kooy 2015). 
 
1.2 
Clinical Manifestation of FXS 
Individuals with FXS are at increased risk for a range of behavioral problems that may limit 
their academic performance, adaptive function, daily living skills, and social interactions. 
Anxiety is the most common behavioral problem in individuals with FXS, with specific 
symptoms of shyness, social anxiety, hyperarousal, and stereotypic behavior such as hand 
flapping and hand biting. Aggressive behaviors in male individuals with FXS are also 
common and may lead to injuries to caregivers, peers, or friends (Wheeler et al 2016). 
Attention-deficit/hyperactivity disorder symptoms (overarousal, hyperactivity, distractibility, 
and impulsivity) may also be noted. Individuals with FXS can experience problems in one or 


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more of these behavior domains. There is a wide range of variability in symptoms, although 
they tend to be more severe in males than in females (Hagerman 2002). 
 
Disordered sleep is a phenotype noted in animal models of FXS, and parents typically report 
sleep problems for their children with FXS (Zhang et al 2008). Studies have estimated that 
31% to 77% of individuals with FXS have sleep problems (Kronk et al 2010). Children with 
FXS typically experience shorter sleep duration, more difficulties settling into sleep, and 
increased wake time after sleep onset (WASO) than unaffected children (Gould et al 2000; 
Richdale 2003). 
 
Current behavior therapy treatments include speech therapy, physical therapy, occupational 
therapy, and educational resources. Current treatments with medications target only the 
behavioral phenotypes and not the underlying brain deficits (Hagerman et al 2009). 
 
1.3 
Background on OV101 
OV101 (gaboxadol) or 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP) was 
synthesized in the late 1970s and has since been used in nonclinical studies as a GABAA 
receptor agonist. More than 1000 publications and reports, including several clinical studies 
in scientific journals, are available. OV101 is the first highly selective, extrasynaptic GABA 
receptor agonist that binds as an orthosteric agonist to the α4- and δ-containing subunit of 
extrasynaptic GABA receptors (Figure 1–1). 


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The investigator’s brochure contains further information on the nonclinical pharmacology 
and toxicology of OV101 (Ovid Therapeutics Inc. 2017). 
Figure 1–1 
Main Sites of Action of OV101, Benzodiazepine, and Novel 
Benzodiazepine-Like Compounds 
 
 
Abbreviations: BZD, benzodiazepine and benzodiazepine-like compounds; GABA, gamma-aminobutyric acid; 
GBX, OV101 (gaboxadol). 
 
 
The affinity of OV101 is 1 to 3 orders of magnitude greater for extrasynaptic receptors 
containing the δ subunit than for the αβγ-containing GABAA receptors that are mainly 
located within the synaptic junction and are the site of the highest modulatory effects of most 
benzodiazepines and benzodiazepine-like compounds (eg, zolpidem). In vitro binding studies 
have shown that gaboxadol binds selectively to the extrasynaptic α4δ-containing GABAA 
receptor subpopulation and possesses no significant affinities for other target receptors in the 
central and peripheral nervous system. Conversely, the presence of α4 or δ subunits in the 
GABA receptor confers insensitivity to benzodiazepines. The mechanism of action of OV101 
is unique among GABAergic agents, including benzodiazepines, zolpidem and other 
zolpidem-like drugs, neurosteroids, and drugs that act on GABA metabolism or uptake. 
In vivo and in vitro studies have shown that neither benzodiazepines nor alcohol potentiate 
the activity of OV101, and in contrast to benzodiazepine receptor agonists, no withdrawal 
effects were observed in animals after chronic dosing with OV101. In drug discrimination 
studies, rats and baboons trained to respond to benzodiazepines did not respond to OV101. 
Furthermore, OV101 did not show abuse potential in baboons trained to self-inject cocaine. 
 


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1.4 
Clinical Experience with OV101 
OV101 was generally safe and well tolerated in all Phase 2 and 3 studies that included more 
than 4300 subjects with insomnia (aged 18 to 64 years) who were administered doses up to 
15 mg (20 mg in one early Phase 2 study). In adult subjects, the most common adverse 
events (AEs) that occurred more frequently in OV101-treated subjects than in subjects on 
placebo were dizziness, nausea, vomiting, somnolence, and headache. Most AEs were of 
mild to moderate intensity. Generally, tolerability was better in male subjects than in female 
subjects, most likely due to the lower body weight of females. 
 
OV101 administration in the morning was safe at all doses (Study 99096). In healthy young 
men, doses up to 20 mg were well tolerated when given alone as single morning doses for 
5 days. In young women, a 15 mg morning dose was not well tolerated or was tolerated with 
considerable discomfort from Day 2 onwards. An evening dose of 15 mg was well tolerated 
in young women and women above 55 years for 3 consecutive days. The AEs with the 
highest incidences in this study were dizziness, nausea, headache, and somnolence. The 
majority of AEs had a rapid onset (within 1 to 2 hours postdose) and resolved after the drug 
was discontinued. 
 
Safety data from Study 11336 showed that 30 mg and 45 mg OV101 in women and 45 mg 
OV101 in men was not tolerated based on their history of hypnotic/sedative abuse or other 
drug abuse. This is contrary to previous experience with the same doses in healthy 
volunteers. These findings suggest that a history of hypnotic/sedative abuse or other drug 
abuse decreases the tolerability of supratherapeutic doses of gaboxadol. Adverse events that 
were associated with lack of tolerability included psychiatric events such as agitation, 
dissociation, hallucinations, disorientation, and anxiety. 
 
Approximately 500 subjects were exposed to OV101 in clinical studies in 
non−insomnia-related development. The safety and tolerability profile of OV101 in the 
non−insomnia-related studies was similar to that in sleep disorder studies. In general, the 
AEs were dose related, with no AEs reported at the 5-mg dose and only mild AEs reported 
for the 10-mg dose of OV101. 
 
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 


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1.5 
Pharmacokinetics in adults and adolescents 
The pharmacokinetic (PK) profile of OV101 was similar regardless of whether it was 
administered in the morning or evening in the fasting state (Study 10218). There were also no 
differences between morning and evening PK when OV101 was given with food. A high-fat 
meal just before OV101 administration in the morning or evening delayed absorption by 0.5 
to 1 hours and decreased the maximum concentration by approximately 30% compared to the 
fasting state, whereas exposure was practically unchanged. 
In adults, OV101 was rapidly absorbed and eliminated when given orally at doses of 10 to 
40 mg. Maximum plasma concentration was reached after 0.5 to 1 hour, and the elimination 
half-life was approximately 1.5 hours. There appeared to be an age effect, with elderly people 
having higher exposure and slightly longer elimination half-lives than younger adults. No 
maintenance) and slow wave sleep, resulting in an improvement in the quality and restorative 
effects of sleep (Roth et al 2010). 
 
Currently, OV101 is being investigated by Ovid for AS and FXS. Results from 
Study OV101-16-001 indicated that a 5-mg dose administered in the morning was well 
tolerated in subjects 13 to 17 years of age with either FXS or AS. One subject experienced 
2 nonserious AEs (flushing, considered to be related to study drug, and injection site 
bruising, considered to be unrelated to study drug) that were mild in intensity. 
 
OV101 has been studied in a 12-week Phase 2 safety and efficacy study in 88 subjects 
(adults and adolescents aged 13 to 49 years) with AS. Fifty-eight subjects were treated with 
OV101 either once-daily (15 mg at bedtime) or twice-daily (10 mg in the morning, 15 mg 
at bedtime), and 29 patients were treated with placebo. Treatment discontinuations due to 
AEs were low (placebo, 1; OV101 once-daily, 0; OV101 twice-daily, 3). The most frequent 
AEs across all treatment groups were vomiting, somnolence, irritability, aggression, pyrexia, 
and upper respiratory infection. The AEs associated with OV101 treatment were similar to 
placebo treatment, with the majority of AEs being mild. Events occurring in >5% (2 or more 
patients) compared to placebo in either treatment arm included pyrexia, rash, seizure, 
enuresis, and myoclonic epilepsy. Two subjects had a SAE of seizure, both of whom had a 
previous history of seizures: 1 subject in the once-daily dose group, deemed unrelated to 
study drug, and treatment was continued; 1 subject in the twice-daily dose group, deemed as 
possibly related to study drug, and treatment was discontinued. Please see the investigator 
brochure for additional information on the study in AS and the benefit risk profile. 
 
 
 
 
 
 
 
 
 
 
 


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were observed with warfarin, digoxin, or paroxetine. An additive effect was observed when 
OV101 was co-administered with alcohol. In the adolescent (13-17 years) PK study 
(OV101-16-001) with subjects with FXS or AS, the PK profile of a single 5 mg dose of 
OV101 appeared comparable to that of young adults in the Lundbeck/Merck studies. 
 
 
 
 
 
 
 
1.6 
Study Rationale and the Role of GABA in FXS 
There is a high unmet medical need for effective therapies targeting the behavior deficits in 
FXS. Current approaches to psychopharmacological treatment (eg, stimulants, mood 
stabilizers, and anxiolytics) for FXS are symptom targeted to manage difficult behaviors 
without regard to the underlying pathophysiology. There is currently no drug approved for 
the treatment of FXS. 
 
The use of OV101 for treatment of individuals with FXS is based on studies in a relevant 
mouse model of the disease, the Fmr1 KO mouse, which lacks FMRP due to a disruption in 
its FMR1 gene. Fmr1 KO mice have decreased GABA synthesis, decreased presynaptic 
GABA release, and decreased extrasynaptic levels of GABA, resulting in decreased tonic 
inhibition. OV101 was shown to restore tonic inhibition in the amygdala, reduce sensory 
hypersensitivity and motor hyperactivity, and improve pre-pulse inhibition (signal to noise 
ratio) in Fmr1 KO mice (Olmos-Serrano et al 2010; Olmos-Serrano et al 2011; Martin et al 
2014). Cogram et al recently presented data that showed full normalization of abnormal 
repetitive, social, and anxiety-like behaviors with OV101 in another FXS KO mouse model, 
the Fmr1 KO2 mouse (Cogram et al 2017). Taken together, these data support the potential 
of OV101 to treat the core behavioral deficits noted in individuals with FXS. Importantly, the 
ability of OV101 to potentiate tonic inhibition is unlike any other GABAergic agent, 
including benzodiazepines, zolpidem, other zolpidem-like drugs, neurosteroids, and drugs 
that act on GABA metabolism or uptake. 
 
In addition to these data on presynaptic dysfunction, additional studies support the potential 
of OV101 in FXS. Chronic treatment in mice resulted in both an increase in hippocampal 
neurogenesis and improved performance in several cognitive tasks (Whissell et al 2013). 
Moreover, OV101 has shown anticonvulsant/anti-epileptic activity in several animal models 
(Kristensen et al 2003; Sun et al 2013; Medrihan et al 2015). 
accumulation was evident after 5 days of multiple dosing. OV101 was almost exclusively 
eliminated via the urine, mainly as the unchanged drug. No clinically relevant interactions 


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This study will enroll only male subjects with FXS. FXS is more common in males, and 
males are more severely affected than females (likely because females have an additional 
X chromosome). Thus, the FXS phenotype in male subjects is expected to be more 
homogeneous than in female subjects, thus leading to a more homogeneous treatment 
response in this early Phase 2 study than would be likely if both male and female subjects 
were enrolled. 
 
The purpose of this study is to investigate the safety, tolerability, and exploratory efficacy of 
treatment by oral administration of OV101 at doses of 5 mg/day (5 mg once a day [QD]), 
10 mg/day (5 mg twice a day [BID]), or 15 mg/day (5 mg three times a day [TID]) in 
adolescent and adult male subjects with FXS. The 12-week, randomized, double-blind, 
parallel-group, proof-of-concept study design will inform OV101 clinical development and 
the design of future studies in FXS. 


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biomarkers, and treatment response 
FXS or treatment response 
levels of OV101 or treatment response 
studies to perform population PK and PK-pharmacodynamic (PD) analysis and to 
evaluate the exposure-response of OV101 in individuals with FXS 
2 
Study Objectives 
2.1 
Primary Objectives 
 To evaluate the safety and tolerability of OV101 over 12 weeks of treatment across 
different daily dosing regimens in adolescent and adult male subjects with FXS 
 
2.2 
Secondary Objectives 
 To evaluate changes in behavior during 12 weeks of treatment with OV101 across 
different daily dosing regimens in adolescent and adult male subjects with FXS 
 
2.3 
Exploratory Objectives 
 To evaluate changes in sleep, adaptive functioning, and quality of life across different 
daily dosing regimens of OV101 treatment over 12 weeks in adolescent and adult 
male subjects with FXS 
 
 




 


 


 


 To explore the relationships among study endpoints (eg, behavior, sleep), where 
appropriate 
 
 


To obtain plasma OV101 concentrations for use in combination with data from other 
To explore the relationships between event related potential (ERP) measurements and 
To explore the relationships among subjects’ microbiomes and clinical presentation of 
To explore the relationships among plasma levels of OV101, metabolomic 
To evaluate possible acute rebound phenomena (eg, sleep disruption or behavioral 
problems) that occur following discontinuation of treatment with OV101 using  
outcome assessments administered at a follow-up visit 4 to 6 weeks after the end of 
treatment  


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3 
Investigational Plan 
3.1 
Study Design 
This is a Phase 2a, randomized, double-blind, parallel-group study to evaluate the safety, 
tolerability, and efficacy of OV101 at 3 daily doses: 5 mg/day (5 mg QD), 10 mg/day (5 mg 
BID), and 15 mg/day (5 mg TID) in adolescent and adult male subjects with FXS. Subjects 
with a clinically and molecularly confirmed diagnosis of FXS will be eligible for inclusion in 
the study (Section 4.1). The study will comprise a screening period of at least 1 week (to 
allow for actigraphs) and up to 3 weeks; a baseline visit on Day 1 for treatment 
randomization (enrollment), baseline assessments, and first dose of study drug; clinic visits 
for safety and efficacy assessments over a 12-week treatment period, including clinic visits at 
Week 2, Week 6, and Week 12 (end-of-treatment [EOT]); and an end-of-study (EOS) follow- 
up visit occurring any time between the ends of Week 16 and Week 18 (Figure 3–1). The 
schedule of activities for this study is fully presented in Table 6-1. 
 
Figure 3–1 
Study Schematic 
 
 
 
 
 
 
 
Abbreviations: AM, morning dose only; BID, twice a day; EOS, end of study; EOT, end of treatment; TID, 
3 times a day. 


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For each subject, after informed consent is obtained (Section 9.3), screening assessments will 
be completed within the 3 weeks preceding Baseline. At Baseline, subjects 13 to 22 years old 
(inclusive) who meet all eligibility criteria (Section 4.1) will be enrolled on Day 1 in a 1:1 
target ratio between adolescents (13 to17 years old, inclusive) and adults (18 to 22 years old, 
inclusive). A sufficient number of subjects will be enrolled to ensure that at least 30 evaluable 
subjects complete 12 weeks of treatment. 
 
Subjects will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups (5 mg QD, 
5 mg BID, and 5 mg TID), stratified by age group (adolescent/adult) to achieve balance 
among treatment arms. There is no placebo group in this study. All subjects will take study 
drug TID (morning, afternoon, and evening), OV101 in the morning and OV101 or placebo 
in the afternoon and evening throughout the treatment period (including Baseline), as 
described in Section 5.2 and Section 5.4.1. There will not be any dose adjustments permitted 
during the study. 
 
After random assignment at Baseline, subjects will receive the assigned package of blinded 
study treatment according to the treatment code for the first 6 weeks of treatment and will 
take their first dose of study drug at the clinic. They will receive another assigned package of 
study treatment at the Week 6 clinic visit. 
 
Each subject (assisted by a legally acceptable representative [LAR]/caregiver) will complete 
paper sleep diaries and wear actigraphs over the 7-day periods immediately preceding 
Baseline and the Week 2, Week 6, EOT, and EOS clinic visits. The Baseline, Week 2, 
Week 6, and EOT visits will be full-day clinic visits. 
 
For each subject, after informed consent is obtained, the maximum duration of individual 
subject participation will be 21 weeks. A subject will have completed the study when he 
completes the EOS visit. The end of the study is defined as the date when the last subject 
completes his last visit (includes follow-up visit). 
 
Safety information will be collected during phone calls at the end of Weeks 1, 4, 8, and 10 
(on Days 8, 29, 57, and 71, respectively), in addition to during every clinic visit (screening, 
baseline, Week 2, Week 6, EOT, and EOS). At the investigator’s discretion, subjects may be 
evaluated at unscheduled clinic visits for reasons related to subject safety. At unscheduled 
visits, subjects will be queried about AEs, changes in concomitant medications, and 
suicidality, and safety laboratory assessments may be conducted. Periodic interim blinded 


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The TID regimen was selected to 
maintain more consistent plasma exposure to OV101, which has a half-life of approximately 
1.5 hours. The QD and BID dosing regimens were selected to evaluate whether OV101 
provides a persistent effect in the absence of detectable plasma concentrations. 
review of safety data will be performed as part of routine pharmacovigilance activities. No 
interim statistical analysis is planned. 
 
Activities during each period of the study are described by study visit in Section 6.1 and are 
presented in greater detail in the workbooks for caregiver/clinician/subject assessments. 
 
3.1.1 
Rationale of Dose Selection 
The total daily doses to be administered in the present study range from 5 mg/day to 
15 mg/day, which are within the dose range previously found to be well tolerated in adult 
subjects. 
 
 
Therefore, OV101 exposure in the present study in adolescent male subjects is 
expected to be comparable to the exposure range previously studied across the Phase 1, 2, 
and 3 studies that evaluated OV101 in adult subjects with insomnia.  
 
Daily doses of 5 mg/day, 10 mg/day, and 15 mg/day will be evaluated with 3 dosing 
regimens: OV101 5 mg QD (morning), BID, and TID. 
 
 
 
After the last dose of study drug during the treatment period (at the EOT clinic visit) there 
will be no tapering of OV101 dosing, as no withdrawal effects have been observed in 
previous clinical studies. 
 
Results from Study OV101-16-001 indicate that the PK profile of OV101 following 
administration of a single 5 mg oral dose to adolescent (13- to 17-year-old) male and female 
subjects with FXS or AS is comparable to the PK profile previously observed in healthy adult 
subjects.  


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4 
Subject Selection and Withdrawal Criteria 
4.1 
Selection of Study Population 
Subjects will be enrolled at approximately 8 sites in the United States and approximately 1 
site in Israel, with a goal of having 30 subjects complete 12 weeks of treatment. Subjects will 
be assigned to study treatment only if they meet all of the 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, 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 of the following criteria to be enrolled in this study. 
 
1. Is male and 13 to 22 years old (inclusive) at the time of informed consent. 
2. Has a diagnosis of FXS with a confirmed FMR1 full mutation (≥200 CGG repeats). 
The diagnosis must be confirmed by genetic testing prior to subject randomization. 
3. Has a Clinical Global Impression-Severity (CGI-S) score of 4 (moderately ill) or 
greater at screening. 
4. Is currently being treated with no more than 3 anti-epileptic and/or psychoactive 
medications, including those prescribed off-label to address behavioral conditions. 
Any concomitant medication, including anti-epileptic and/or behavioral medications, 
supplements, and special diets, must be at a stable dose for at least 4 weeks before 
screening and must be maintained at that dose throughout the duration of the study. 
5. Has an LAR/caregiver capable of providing informed consent and able to attend all 
scheduled study visits, oversee the administration of study drug, and provide feedback 
regarding the subject’s behavior and other symptoms as described in the protocol. 
6. Provide assent to the protocol (to the extent possible and in accordance with local 
institutional review board [IRB] and regulatory requirements) and have an 
LAR/caregiver who will provide written informed consent. Subjects providing assent 
must do so at the same visit as LAR/caregiver written informed consent is provided. 


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7. Is able to attend all scheduled study visits and willing and capable of performing the 
required study assessments. 
8. Is able to ingest the study drug capsules (including sprinkling capsule contents onto 
1 spoon of applesauce or low-fat yogurt). 
9. Has an intelligence quotient (IQ) less than 75 as measured by the Stanford-Binet-5 
(SB-5) at screening or a previously documented SB-5 measurement conducted within 
6 months of the screening visit. For the site in Israel, please see Appendix for site- 
specific details regarding the IQ test. 
10. Will agree to remain sexually abstinent from the first day of screening until 30 days 
after the last dose of study treatment. 
11. Has LAR/caregivers who will agree not to post any of the subject’s personal medical 
data related to the study or information related to the study on any website or social 
media site (eg, Facebook and Twitter) until they have been notified that the study is 
completed. 
4.1.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
 
1. Has a concomitant disease (eg, gastrointestinal, renal, hepatic, endocrine, respiratory, 
or cardiovascular system disease) or 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 this study. 
2. Has clinically significant lab abnormalities or vital signs at the time of screening (eg, 
alanine aminotransferase or aspartate aminotransferase >2.5 × upper limit of normal; 
total bilirubin or creatinine >1.5 × upper limit of normal). Re-testing of safety labs 
may be allowed after consultation with the medical monitor or designee. 
3. Uses any GABAergic agent (eg, acamprosate, baclofen, vigabatrin, tiagabine, riluzole, 
benzodiazepines, and gabapentin) on a regular schedule. Benzodiazepines 
administered for situational anxiety (eg, for occasional procedures or events) are 
permitted. 
4. Uses any cannabinoid derivatives. 


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5. Has a history of uncontrollable seizure disorder or seizure episodes within 6 months of 
screening or change in the anticonvulsant pharmacotherapy in the past 3 months. 
6. Has a history of suicidal behavior or considered by the investigator to be at high risk 
of suicide. 
7. Has any condition or there is any reason that, in the opinion of the investigator, makes 
the subject unsuitable for enrollment. 
8. Is unable or does not have an LAR/caregiver able to comply with study requirements. 
9. Has enrolled in any clinical trial or used any investigational agent, device, and/or 
investigational procedure within the 30 days before screening or does so concurrently 
with this study. 
10. Is a family member of the investigator or study site personnel. 
4.2 
Discontinuation of Subjects From Study Treatment and the Study 
Discontinuation of a subject from treatment early (before Week 12) for any reason will 
initiate procedures for discontinuation of the subject from the study, including EOT and EOS 
visits (Section 3.1). For subjects for whom study treatment is stopped early (before Week 12), 
an EOT visit should be conducted within 2 weeks after the last day of study medication. 
After completing the EOT visit, an EOS visit should be completed within 4 to 6 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 visit. 
 
4.2.1 
Reasons for Withdrawal/Discontinuation 
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. 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. 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 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. 


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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 (eg, 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 Ovid 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. Any subject may withdraw his or her consent at any time. 
 
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 
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 serious AE (SAE). In every case, efforts must be made to undertake protocol-specified 
safety follow-up procedures. 


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4.2.3 
Replacements 
A sufficient number of subjects will be enrolled to ensure that at least 30 evaluable subjects 
complete 12 weeks of treatment. 
 
Subjects who fail to satisfy all inclusion and exclusion criteria at screening may be 
rescreened 1 additional time at the discretion of the medical monitor or his designee. 


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5 
Study Treatments 
5.1 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet all eligibility criteria will be randomly assigned at Baseline to the 
5 mg/day, 10 mg/day, or 15 mg/day OV101 treatment group in a 1:1:1 allocation ratio. It is 
anticipated that approximately 36 male subjects will be enrolled (to obtain 30 evaluable 
subjects), while maintaining a 1:1 target ratio between adolescents (13 to17 years old, 
inclusive) and adults (18 to 22 years old, inclusive). The randomization schedule will be 
stratified by age (13 to 17, inclusive; 18 to 22, inclusive). It will also use an appropriate block 
size, which will not be revealed. 
 
An interactive web response system (IWRS) will be used to administer the randomization 
schedule. The PPD 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 
Treatments Administered 
Subjects will take all doses orally (assisted by an LAR/caregiver, if necessary) TID (morning, 
afternoon, evening), at approximately the same times each day, for the duration of the 
12-week treatment period. The morning and afternoon doses should be taken with light low- 
fat food (a glass of low-fat milk would qualify as food), and the afternoon dose should be 
taken at least 6 hours after the morning dose. The evening dose should be taken 30 minutes 
before bedtime. Capsules may be opened and the contents sprinkled onto 1 teaspoon of low- 
fat semiliquid food (eg, 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 specifically how each capsule was taken (eg, 
swallowed whole or taken in 1 teaspoon of semiliquid food). 
 
5.3 
Description of Study Drug 
OV101 is formulated as the monohydrate form (4,5,6,7-tetrahydro-isoxazolo[5,4-c]-pyridin- 
3-ol, monohydrate) in a white size 2 capsule. The capsule contains 5.645 mg of OV101 
monohydrate, which corresponds to 5.0 mg of OV101 (Table 5-1). 


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o 
y 
r 
 
 
 
 
 
Component 
 
 
Function  
 
Amount (mg) 
 OV101a 
 
 Active compound 
 
 5.645 
 
 
 
 
 
 
 
 
 Microcrystalline cellulose  
 Diluent 
 
 138.6 
 
 
 
 
 
 
 
 
 Magnesium stearate 
 
 Lubricant 
 
 0.725 
 
 
 
 
 
 
 
 
 Size 2 hard-gelatin capsule
a 
Delivered as the zwitte
1.129 g of the zwitterio
 
rion mon 
n monoh 
 – 
hydrate. One gram of th 
drate. 
 
e anhydrous f 
 60 
ee zwitterion is equivalent to 
 
 
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. 
 
will manufacture the OV101 and placebo 
capsules.  
 
5.4 
Management of Clinical Supplies 
Bulk capsules, both active and placebo, will be shipped to 
will package and label blinded kits. 
blinded kits directly to each study site according to instructions from the IWRS. 
 
 
 
will ship the 
 
5.4.1 
Study Drug Packaging and Storage 
Study drug will be supplied as 5-mg capsules of OV101 and matching placebo capsules in 
bottles. Bottles will have “Morning,” “Afternoon,” or “Evening” printed on their labels, 
which will be tinted specific colors for the morning, afternoon, and evening doses. Each 
LAR/caregiver will receive a 6-week supply of capsules in a package containing 
1 “Morning” bottle, 1 “Afternoon” bottle, and 1 “Evening” bottle at the baseline visit and at 
the Week 6 visit. 
 
Study drug will be packaged to enable administration for each treatment group regimen 
(Table 5-2). 
Pharmaceutical Composition of OV101 for the 5-mg Capsule 
Table 5-1 
Yourway Transport 
Yourway Transport (Allentown, 
PA). Yourway Transport 
Metrics Contract Services (Greenville, NC) 


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Table 5-2 
Treatment Group Regimens 
 
Treatment Group 
Morning Dose 
Afternoon Dose 
Evening Dose 
5 mg/day OV101 
5-mg OV101 capsule 
Placebo capsule 
Placebo capsule 
10 mg/day OV101 
5-mg OV101 capsule 
Placebo capsule 
5-mg OV101 capsule 
15 mg/day OV101 
5-mg OV101 capsule 
5-mg OV101 capsule 
5-mg OV101 capsule 
 
 
A clinical label will be affixed to the outside of each bottle and each package of 3 bottles. 
The label will specify the sponsor name (Ovid Therapeutics Inc.); subject number; protocol 
number; bottle number (based on randomization); number of capsules (each bottle); 
“Morning,” “Afternoon,” or “Evening”; and “Take as directed.” Bottles and study treatment 
will be distributed by unique subject numbers and bottle numbers as designated by the 
IWRS, and bottle quantities will be supplied to each study center in accordance with the 
IWRS. The recommended storage conditions and expiry date (where required) will be stated 
on the product label. At the study site, study drug must be stored in a secure area (eg, a 
locked cabinet), protected from moisture, and kept at a controlled room temperature, 59°F to 
77°F. 
 
Subjects and LAR/caregivers must keep all study drugs in the original bottles. 
 
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 
Other Supplies 
Actigraphs 
 
 
Section 6.3.3.1) will be supplied to study sites by Philips 
Respironics Inc (Murrysville, PA). Philips Respironics Inc will be responsible for device 
maintenance during the study and device retrieval at the end of the study. 
(Philips Actiwatches; 


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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 associated with a SAE must be 
promptly reported to the Ovid/Sciformix Safety Hotline (Section 6.6.1.5). Overdoses 
without signs or symptoms do not need to be recorded as AEs; any AEs associated with the 
overdose should be reported on the relevant AE/SAE sections in the eCRF. 
 
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 medication compliance and medication errors. The medication diary will be reviewed at 
each clinic visit 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 
The most likely symptomatic medication error will be overdose (Section 5.5.1). 
 
5.6 
Blinding 
The study will be performed in a double-blind manner, 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. 
 
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. In the event that the blind needs to be 
broken because of a medical emergency, the investigator may unblind an individual subject’s 
treatment allocation. Before unblinding a subject’s treatment assignment and as soon as 


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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 the IWRS. 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. 
 
5.7 
Treatment Compliance 
Subject compliance will be determined by comparing the capsule counts of returned study 
drug bottles at Week 6 and EOT to the capsule count of study drug dispensed. The number of 
capsules remaining will be tracked and recorded by individual bottle (labeled “Morning,” 
“Afternoon,” or “Evening”). The LAR/caregiver will be questioned as to the reason(s) why 
remaining capsules have not been administered (eg, forgot, subject refused, subject had side 
effects so parent decided to give a drug holiday), and the approximate date and time of any 
missed doses will 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 (eg, speech therapy, physical therapy, occupational therapy) for 4 weeks before 
screening and should remain on the stable regimens until after the EOS 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 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 (eg, acamprosate, baclofen, vigabatrin, tiagabine, riluzole, 
benzodiazepines, 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. 
 
Use of cannabinoid derivatives is prohibited during the course of the study. 
Use of other investigational agents is prohibited during the course of the study. 
5.8.2 
Restrictions 
Any concomitant medication, including anti-epileptic and/or behavioral medications, 
supplements, and special diets, must be at a stable dose for at least 4 weeks before screening 
and must be maintained throughout the duration of the study. 
 
Each subject may be treated concurrently with no more than 3 anti-epileptic and/or 
psychoactive medications, including those prescribed off-label to address behavioral 
conditions. 
 
Benzodiazepines administered for situational anxiety (eg, for occasional procedures or 
events) are permitted. Subjects should not consume alcohol during the course of the study. 


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6 
Study Assessments and Procedures 
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 
workbooks for caregiver/clinician/subject assessments. 


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Table 6-1 
Schedule of Activities by Clinic Visit 
 
Visit Name 
Screening 
Baseline 
Phone 1 
Week 2 
Phone 4 
Week 6 
Phone 8 
Phone 10 
EOT 
EOS 
Window (days) 
–a 
– 
±2 
±3 
±2 
±3 
±2 
±2 
±3 
+14 
Dayb 
–21 to 1 
1 
8 
15 
29 
43 
57 
71 
85 
113 
Week 
– 
0 
1 
2 
4 
6 
8 
10 
12 
16c 
Obtain informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
Verify inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Obtain medical history 
X 
Xd 
 
 
 
 
 
 
 
 
Conduct clinical assessmente for FXS 
X 
 
 
 
 
 
 
 
 
 
Stanford-Binet-5 or previous SB-5 documentationf 
X 
 
 
 
 
 
 
 
 
 
Review for DSM-5 autism spectrum disorder 
criteria 
X 
 
 
 
 
 
 
 
 
 
Molecular FXS Testg 
X 
 
 
 
 
 
 
 
 
 
PK sampling 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 Biomarker assessment (plasma, cheek swab;  
 optional)  
Clinical assessment of suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
Xd 
 
X 
 
X 
 
 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
X 
X 
Clinical laboratory tests 
X 
Xd 
 
X 
 
X 
 
 
X 
 
Randomization assignment 
 
X 
 
 
 
 
 
 
 
 
Adverse event inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication inquiry 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense medication diary 
 
X 
 
 
 
X 
 
 
 
 
Review/collect medication diary, assess compliance  
 
 
X 
 
X 
 
 
X 
 
Dispense study drug 
 
X 
 
 
 
X 
 
 
 
 
Collect unused study drug 
 
 
 
 
 
X 
 
 
X 
 


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Visit Name 
Screening 
Baseline 
Phone 1 
Week 2 
Phone 4 
Week 6 
Phone 8 
Phone 10 
EOT 
EOS 
Window (days) 
–a 
– 
±2 
±3 
±2 
±3 
±2 
±2 
±3 
+14 
Dayb 
–21 to 1 
1 
8 
15 
29 
43 
57 
71 
85 
113 
Week 
– 
0 
1 
2 
4 
6 
8 
10 
12 
16c 
Caregiver-Completed Measures 
 
 
 
 
 
 
 
 
 
 
Aberrant Behavior Checklist-Community 
 
X 
 
X 
 
X 
 
 
X 
X 
Anxiety, Depression, and Mood Scales 
 
X 
 
X 
 
X 
 
 
X 
X 
Repetitive Behavior Scale-Revised 
 
X 
 
X 
 
X 
 
 
X 
X 
Conners 3rd Edition 
X (LF) 
X (SF) 
 
X (SF) 
 
X (SF) 
 
 
X (SF) 
X (SF) 
Short Sensory Profile-2 
 
X 
 
X 
 
X 
 
 
X 
X 
Children’s Sleep Habits Questionnaire 
 
X 
 
X 
 
X 
 
 
X 
X 
Sleep diary issuedh 
X 
X 
 
X 
 
X 
 
 
X 
 
Sleep diary collected and reviewed 
 
X 
 
X 
 
X 
 
 
X 
X 
BASC-3 Parenting Relationship Questionnaire 
X 
X 
 
 
 
X 
 
 
X 
 
Parent Global Impressions-Severity 
X 
X 
 
X 
 
X 
 
 
X 
X 
Parent Global Impressions -Improvement 
 
 
 
X 
 
X 
 
 
X 
X 
Pediatric Quality of Life Inventory 
 
X 
 
 
 
X 
 
 
X 
X 
Clinician-Completed Measures 
 
 
 
 
 
 
 
 
 
 
Pediatric Sleep CGI structured sleep history 
Xi 
Xj 
 
Xj 
 
Xj 
 
 
Xj 
Xj 
Pediatric Sleep CGI-Severity 
X 
X 
 
X 
 
X 
 
 
X 
X 
Pediatric Sleep CGI-Improvement 
 
X 
 
X 
 
X 
 
 
X 
X 
Caregiver top 3 concerns visual analog scale 
 
X 
 
X 
 
X 
 
 
X 
X 
Vineland Adaptive Behavior Scale, 3rd Edition 
 
X 
 
 
 
X 
 
 
X 
 
CGI-Severity 
X 
X 
 
X 
 
X 
 
 
X 
X 
CGI-Improvement 
 
 
 
X 
 
X 
 
 
X 
X 


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Visit Name 
Screening 
Baseline 
Phone 1 
Week 2 
Phone 4 
Week 6 
Phone 8 
Phone 10 
EOT 
EOS 
Window (days) 
–a 
– 
±2 
±3 
±2 
±3 
±2 
±2 
±3 
+14 
Dayb 
–21 to 1 
1 
8 
15 
29 
43 
57 
71 
85 
113 
Week 
– 
0 
1 
2 
4 
6 
8 
10 
12 
16c 
Subject-Completed Measures 
 
 
 
 
 
 
 
 
 
 
Actigraph issued 
X 
X 
 
X 
 
X 
 
 
X 
 
Actigraph and actigraphy data collectedk 
 
X 
 
X 
 
X 
 
 
X 
X 
KiTAP 
X 
X 
 
 
 
X 
 
 
X 
X 
RBANS 
X 
X 
 
 
 
X 
 
 
X 
X 
Event related potential (optional) 
 
X 
 
 
 
X 
 
 
X 
 
Abbreviations: BASC-3, Behavior Assessment System for Children, 3rd Edition; CGI, clinical global impressions; DSM-V, Diagnostic and Statistical Manual of Mental Disorders; 
EOS, end of study; EOT, end of treatment; FXS, fragile X syndrome; KiTAP, Test of Attentional Performance for Children; LF, long form; PK, pharmacokinetic; RBANS, 
Repeatable Battery for the Assessment of Neuropsychological Status; SF, short form. 
Note: At the investigator’s discretion, subjects may be evaluated at unscheduled clinic visits for reasons related to subject safety. At unscheduled visits, subjects will be queried 
about AEs, changes in concomitant medications, and suicidality, and safety laboratory assessments may be conducted. 
a 
Screening is to be conducted for up to 21 days (inclusive) before Day 1; subjects who meet all entry criteria can be randomly assigned at any time during the screening period. 
b 
There is no Day 0. The screening period can start up to 21 days before Day 1. 
c 
The EOS visit may occur 4 to 6 weeks after the EOT visit, between the end of Week 16 and the end of Week 18 for subjects who do not stop treatment early. 
d 
If the screening and baseline visits can be completed within 10 days, the following procedures do not need to be repeated at the baseline visit: medical history, physical 
examination, clinical laboratory tests and determination of concomitant medications. 
e 
Signs and symptoms of FXS. 
f 
For the site in Israel, please see Appendix for site-specific details regarding the IQ test. 
g 
Only if no written evidence for molecular diagnosis is available in the subject’s records. 
h 
The sleep diary is to be completed over the 7-day periods immediately preceding Day 1 and the Week 2, Week 6, EOT, and EOS clinic visits; a calendar will be issued to 
ensure that the diary information collection starts on the appropriate days. 
i 
At the initial screening visit, the clinician will complete parts A, B, and C of the structured sleep history form. 
j 
At clinic visits after the screening visit, the clinician will complete only part A of the structured sleep history form. 
k 
The actigraph is to be worn and actigraphy data are to be collected for the 7-day periods immediately preceding Day 1 and the Week 2, Week 6, EOT, and EOS clinic visits; a 
calendar will be issued to ensure that the subject starts wearing the actigraph on the appropriate days. 


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6.1 
Study Visits 
After the screening period, each subject will be scheduled for 5 clinic visits and 4 phone 
visits (Table 6-1). At the investigator’s discretion, subjects may be evaluated at unscheduled 
clinic visits for reasons related to subject safety. At unscheduled visits, subjects will be 
queried about AEs, changes in concomitant medications, and suicidality, and safety 
laboratory assessments may be conducted. 
 
6.1.1 
Screening Period 
All subjects will be screened for participation in the study up to 21 days before Baseline, 
when the first dose will be administered. Subjects who meet all entry criteria can be 
randomly assigned at any time during the screening period. 
 
Written informed consent (from the subject’s LAR/caregiver) and assent (from the subject) 
will be obtained before the subject participates in any study procedure and begins the study 
screening procedures for eligibility. Assent will be obtained if the investigator believes that 
the subject can provide it (depending on the subject’s intellectual ability), but assent may not 
be relevant based on the subject’s intellectual disability and/or age (Section 9.3). 
 
During the screening period, the investigator will determine whether the LAR/caregiver and 
subject are able to complete all questionnaires and assessments that require their 
contributions and will also assess their ability to comply with study procedures. Screening of 
siblings will require approval from the medical monitor or his designee. 
 
For those subjects without documentation of a molecularly confirmed diagnosis of FXS, 
blood samples will be obtained during the screening period to confirm the molecular 
diagnosis of FXS. 
 
In preparation for participation in this trial, LAR/caregivers will be educated on the clinical 
safety data for OV101 obtained thus far and will be trained to report efficacy assessments and 
to identify, manage, and report any potential AEs. 
 
The LAR/caregiver will be provided with a sleep diary for documenting the subject’s sleep 
and 1 wearable actigraph (Section 6.3.3) to document daily and nocturnal activities and sleep 
pattern. The subject will wear the actigraphy device and the LAR/caregiver will record data 


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ERP (if applicable consent provided). 
in the sleep diary for at least 7 days before each study visit. A calendar reminder will also be 
provided for starting actigraph use and recording data in the sleep diary. 
 
A subject who does not meet the inclusion criteria or who meets an exclusion criterion will 
be considered a screen failure. Whether rescreening is acceptable will be discussed with the 
medical monitor. Rescreening may be allowed under circumstances in which the subject 
passed screening but could not be randomly assigned within the 21-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 (Section 4.2.3). 
 
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. 
 
6.1.2 
Baseline Visit 
Screened subjects will return to the study center for the baseline (Day 1) visit. The 
LAR/caregiver will bring the subject’s completed sleep diary and actigraph, and study staff 
will manage the sleep diaries and actigraphs during the visit as detailed in Section 6.1.2.1. 
Prior to randomized assignment of study regimen, study center staff must confirm 
appropriate completion of the sleep diary, proper recording of the actigraph, and fulfilment of 
all eligibility criteria (Section 4.1). 
 
Subjects who meet all eligibility criteria will be randomly assigned to treatment at Baseline 
as described in Section 5.1. After assignment at Baseline, subjects/caregivers will receive the 
IWRS-assigned package of blinded study treatment according to the treatment code for the 
first 6 weeks of treatment. 
 
The following schedule of activities should be observed for subjects at the baseline visit: 
 
1. Subject should eat a light low-fat breakfast (eg , cereal with low-fat milk, bagel 
with low-fat cream cheese, low-fat yogurt) before coming to the clinic. 
 
2. Study staff conduct the following assessments that involve subject participation, in 
the following order: Test of Attentional Performance for Children (KiTAP),  
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and 
 


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laboratory tests (Section 6.9) are performed. 
3. Morning dose is administered in the clinic (study staff will record time and date). On 
all clinic visit days, the morning dose must be administered before noon. 
 
4. 
 
 
5. Subject optionally eats a light low-fat snack.  
 
6. 
 
Subject vital sign measurements, urine sampling, 
can be completed at any time during the visit. The LAR/caregiver 
questionnaires and investigator/study staff queries of the LAR/caregiver concerning AEs, 
concomitant medications, and subject suicidality (Section 6.8) can also be completed at any 
time during the visit.  
 
The subject and his LAR/caregiver will be expected to complete the Baseline dosing 
(afternoon and evening doses) and continue study drug administration for the remainder of 
the study. 
 
Details of the order of activities and instructions for assessments are provided in the 
workbooks for caregiver/clinician/subject assessments. 
 
Screening and baseline assessments must be performed within a 21-day period. If the 
screening and baseline visits can be completed within 10 days, the following assessments do 
not need to be repeated at the baseline visit: medical history, physical examination, clinical 
laboratory tests, and determination of concomitant medications. 
 
6.1.2.1 
Management of Sleep Diary and Actigraph 
6.1.2.1.1 
Sleep Diary 
Study staff will collect the sleep diary for recording in the eCRF and will review the sleep 
diary for completeness. If quality issues are detected, study staff will again instruct the 
LAR/caregiver in the proper use of the sleep diary. 
and cheek swab (if applicable based on 
At 3 to 4 hours postdose, PK blood sampling is performed. 
At 0.5 to 0.75 hours postdose, PK blood sampling and blood sampling for clinical 


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A new sleep diary will be issued to the LAR/caregiver for use in the 7-day period preceding 
the Week 2 clinic visit. A calendar reminder will also be provided for the start of sleep diary 
assessments. 
 
6.1.2.1.2 
Actigraph 
Study staff will upload data from the subject’s actigraph as described in the study manual and 
will review the quality of the data. If quality issues are detected, study staff will review 
proper use of the actigraph with the LAR/caregiver. Study staff will issue a fully charged, 
reset actigraph to the LAR/caregiver, including new hospital bands (if needed; Section 6.3.3), 
for use in the 7-day period preceding the Week 2 clinic visit. A calendar reminder will also be 
provided for the start of actigraph use. 
 
Study staff will reset and recharge the actigraph received from the LAR/caregiver, and that 
reset and recharged actigraph will be issued for use by the next available subject and 
LAR/caregiver. 
 
6.1.3 
Phone Visits to Assess Safety 
Safety information will be collected during phone calls at the end of Weeks 1, 4, 8, and 10 
(on Days 8, 29, 57, and 71, respectively). The LAR/caregivers will be queried about AEs, 
concomitant medications, and subject suicidality (Section 6.8). 
 
6.1.4 
Week 2 Clinic Visit 
The subject will arrive at the clinic without having taken his morning dose of study 
medication, and study staff will record the actual date and time of his last previous dose of 
study drug. The subject’s LAR/caregiver will bring the study medication to the clinic and the 
morning dose will be administered at the clinic. The subject’s LAR/caregiver will bring the 
subject’s completed sleep diary and actigraph, and study staff will manage the sleep diary 
and actigraph during the visit as detailed in Section 6.1.4.1. 
 
The following schedule of activities should be observed for subjects at the Week 2 clinic 
visits: 
 
1. Subject should have fasted overnight before coming to the clinic. 


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laboratory tests (Section 6.9) are performed. 
2. Morning dose is administered in the clinic (study staff will record time and date). On 
all clinic visit days, the morning dose must be administered before noon. 
 
3. 
 
 
4. Subject should eat a light low-fat breakfast (eg, cereal with low-fat milk, bagel with 
low-fat cream cheese, low-fat yogurt). 
 
5. 
 
Subject vital sign measurements and urine sampling can be completed at any time during the 
visit. The LAR/caregiver questionnaires and investigator/study staff queries of the 
LAR/caregiver concerning AEs, concomitant medications, and subject suicidality 
(Section 6.8) can also be completed at any time during the visit. Any unacceptable 
tolerability of study drug assessed at this visit (eg, somnolence, dizziness, vomiting, or 
change in behavior) must be reported as an AE. 
 
The subject and his LAR/caregiver will be expected to complete the dosing for the day of the 
Week 2 clinic visit (afternoon and evening doses) and continue study drug administration for 
the remainder of the treatment period. 
 
Details of the order of activities and instructions for assessments at the Week 2 clinic visit are 
provided in the workbooks for caregiver/clinician/subject assessments. 
 
6.1.4.1 
Management of Sleep Diary and Actigraph 
6.1.4.1.1 
Sleep Diary 
Study staff will collect, review, and issue a new sleep diary, as described for the baseline 
(Day 1) visit (Section 6.1.2.1.1). 
 
6.1.4.1.2 
Actigraph 
Study staff will upload data and issue a new actigraph, as described for the baseline (Day 1) 
visit (Section 6.1.2.1.2). 
At 3 to 4 hours postdose, PK blood sampling is performed. 
At 0.5 to 0.75 hours postdose, PK blood sampling and blood sampling for clinical 


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completed consent) 
and ERP (if applicable consent provided). 
laboratory tests (Section 6.9) are performed. 
6. At 3 to 4 hours postdose, PK blood sampling is performed. 
6.1.5 
Week 6 Clinic Visit 
The subject will arrive at the clinic without having taken his morning dose of study 
medication, and study staff will record the actual date and time of his last previous dose of 
study drug. The subject’s LAR/caregiver will bring the subject’s original study drug bottles 
(containing any unused study drug) to be collected by the study staff. The LAR/caregivers 
will also bring the subject’s completed sleep diary and actigraph, and study staff will manage 
sleep diaries and actigraphs during the visit as detailed in Section 6.1.5.1. 
 
Based on the returned study drug, study staff will assess compliance and counsel the 
LAR/caregiver on proper administration of study drug, as needed. Study staff will enter the 
capsule counts for each bottle in the eCRF. Study staff will dispense (to the LAR/caregiver) 
the IWRS-assigned package of blinded study treatment for the subject’s second 6 weeks of 
treatment. 
 
The following schedule of activities should be observed for subjects at the Week 6 clinic 
visit: 
 
1. Subject should have fasted overnight before coming to the clinic. 
 
2. Morning dose is administered in the clinic (study staff will record time and date). On 
all clinic visit days, the morning dose must be administered before noon. 
 
3. 
 
 
4. Subject should eat a light low-fat breakfast (eg, cereal with low-fat milk, bagel with 
low-fat cream cheese, low-fat yogurt).  
 
5. Study staff conduct the following assessments that involve subject participation, in 
the following order: KiTAP), RBANS, 
 
 
Subject vital sign measurements, urine sampling, 
can be completed at any time during the visit. The LAR/caregiver 
questionnaires and investigator/study staff queries of the LAR/caregiver concerning AEs, 
At 0.5 to 0.75 hours postdose, PK blood sampling and blood sampling for clinical 
and cheek swab (if applicable based on 


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concomitant medications, and subject suicidality (Section 6.8) can also be completed at any 
time during the visit. Any unacceptable tolerability of study drug assessed at this visit (eg, 
somnolence, dizziness, vomiting, or change in behavior) must be reported as an AE. 
 
The subject and his LAR/caregiver will be expected to complete the dosing for the day of the 
Week 6 clinic visit (afternoon and evening doses) and continue study drug administration for 
the remainder of the treatment period. 
 
Details of the order of activities and instructions for assessments at the Week 6 clinic visit are 
provided in the workbooks for caregiver/clinician/subject assessments. 
 
6.1.5.1 
Management of Sleep Diary and Actigraph 
6.1.5.1.1 
Sleep Diary 
Study staff will collect, review, and issue a new sleep diary, as described for the baseline 
(Day 1) visit (Section 6.1.2.1.1). 
 
6.1.5.1.2 
Actigraph 
Study staff will upload data and issue a new actigraph, as described for the baseline (Day 1) 
visit (Section 6.1.2.1.2). 
 
6.1.6 
End-of-Treatment Visit 
The EOT visit is to be scheduled to occur at the end of Week 12. For subjects for whom study 
drug administration is stopped early (before Week 12), an EOT study visit should be 
conducted within 2 weeks after the last day of study medication. 
 
The subject will arrive at the clinic without having taken his morning dose of study 
medication, and study staff will record the actual date and time of his last previous dose of 
study drug. The subject’s LAR/caregiver will bring the subject’s original study drug bottles 
(containing any unused study drug) to be collected by the study staff. Study staff will assess 
compliance with dosing instructions, entering the capsule count for each bottle in the eCRF. 
 
The LAR/caregiver will also bring the subject’s sleep diary and actigraph, and study staff 
will manage the sleep diary and actigraph during the visit as detailed in Section 6.1.6.1. 
 
The following schedule of activities should be observed for subjects at the EOT clinic visit: 


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completed consent) 
laboratory tests (Section 6.9) are performed. 
provided). 
1. Subject should have fasted overnight before coming to the clinic. 
 
2. Morning dose is a dministered in the clinic (study staff will record time and 
date). On all clinic visit days, the morning dose must be administered before 
noon. 
 
3.  
 
 
4. Subject should eat a light low-fat breakfast (eg, cereal with low-fat milk, bagel 
with low-fat cream cheese, low-fat yogurt).  
 
5. Study staff conduct the following assessments that involve subject participation, 
in the following order: KiTAP,  RBANS, and ERP (if applicable consent 
 
6. 
 
Subject vital sign measurements, urine sampling, and cheek swab (if applicable based on 
can be completed at any time during the visit. The LAR/caregiver 
questionnaires and investigator/study staff queries of the LAR/caregiver concerning AEs, 
concomitant medications, and subject suicidality (Section 6.8) can also be completed at any 
time during the visit. Any unacceptable tolerability of study drug assessed at this visit (eg, 
somnolence, dizziness, vomiting, or change in behavior) must be reported as an AE. 
 
Details of the order of activities and instructions for assessments at the EOT visit are 
provided in the workbooks for caregiver/clinician/subject assessments. 
 
6.1.6.1 
Management of Sleep Diary and Actigraph 
6.1.6.1.1 
Sleep Diary 
Study staff will collect, review, and issue a new sleep diary, as described for the baseline 
(Day 1) visit (Section 6.1.2.1.1). 
 
6.1.6.1.2 
Actigraphs 
Study staff will upload data and issue a new actigraph, as described for the baseline (Day 1) 
visit (Section 6.1.2.1.2). 
At 3 to 4 hours postdose, PK blood sampling is performed. 
At 0.5 to 0.75 hours postdose, PK blood sampling and blood sampling for clinical 


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The purpose of the EOS visit is to evaluate for possible acute rebound phenomena (eg, sleep 
6.1.7 
End-of-Study Visit 
 
disruption and behavior problems) that occur following discontinuation of study drug. The 
EOS visit will be scheduled to be completed within 4 to 6 weeks after the subject completes 
the EOT study visit, any time between the ends of Week 16 and Week 18. For subjects for 
whom study drug administration is stopped early and an early EOT visit occurred, an EOS 
visit should be completed within 4 to 6 weeks after completing the early EOT study visit. 
 
The subject’s LAR/caregiver will bring the subject’s sleep diary and actigraph (issued at the 
EOT clinic visit), and study staff will manage the sleep diary and actigraph during the visit as 
detailed in Section 6.1.7.1. 
 
The following schedule of activities should be observed for subjects at the EOS clinic visit: 
 
 Study staff conduct the following assessments that involve subject participation, in the 
following order: KiTAP and RBANS. 
 
The LAR/caregiver questionnaires and investigator/study staff queries of the LAR/caregiver 
concerning AEs, concomitant medications, and subject suicidality (Section 6.8) can be 
completed at any time during the visit. 
 
Details of the order of activities and instructions for assessments at the EOS clinic visit are 
provided in the workbooks for caregiver/clinician/subject assessments. 
 
6.1.7.1 
Management of Sleep Diary and Actigraph 
6.1.7.1.1 
Sleep Diary 
Study staff will collect the sleep diary for recording in the eCRF. 
 
6.1.7.1.2 
Actigraph 
Study staff will upload data from the subject’s actigraph as described in the study manual. 
 
Actigraphs collected at the EOS clinic visit will be reset and recharged for re-issue and use 
by the next available subject and LAR/caregiver. 


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(Riverside Publishing, Rolling Meadows, 
6.2 
Screening Assessments 
6.2.1 
Autism Spectrum Disorder 
The investigator or qualified designee will review the Diagnostic and Statistical Manual of 
Mental Disorders (DSM-5) criteria for autism spectrum disorder for each subject, specifically 
assessing social communication deficits and restricted/repetitive behaviors and interests. 
 
6.2.2 
Intelligence Quotient 
The SB-5 will be completed only if needed at screening to document that the subject meets 
Inclusion Criterion 9, ie, the subject has an IQ less than 75. Standardized administration of 
the SB-5 begins by administering 2 routing subtests (1 from each of the verbal and nonverbal 
IQ domains) and using these routing subtest scores to determine the start points for the 
remaining verbal and nonverbal domains. Participants will be administered the complete SB- 
5 following standardized administration procedures 
IL). If a participant is not able to complete the entire SB-5, the abbreviated battery IQ will be 
calculated from the 2 routing subtests. The abbreviated battery IQ provides a quick estimate 
of 2 major cognitive factors: fluid reasoning and crystallized ability. 
 
A previous SB-5 documentation (within the 6 months before the screening visit) can be used 
to qualify the subject as having an IQ less than 75. 
 
For the site in Israel, please see Appendix for site-specific details regarding the IQ test. 
 
6.3 
Efficacy Assessments 
Efficacy assessments will be conducted according to the schedule presented in Table 6-1. The 
efficacy assessments, grouped by efficacy domain and participant source, are presented in 
Table 6-2. Every effort should be made to have the same LAR/caregiver complete the parent- 
reported questionnaires. Additionally, every effort should be made to have the same 
Investigator and raters complete the clinician assessments. 


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Table 6-2 
Efficacy Assessments by Domain and Participant Source 
 
Domain 
LAR/Caregiver Assessment 
Clinician Assessment 
Direct Subject 
Assessment 
Behavior 
 
ABC-C 
 
ADAMS 
 
RBS-R 
 
Conners 3rd Edition 
 
Short Sensory Profile-2 
 
 
Sleep 
 
Children’s Sleep Habit 
Questionnaire 
 
Sleep diary 
 
Pediatric Sleep CGI scales 
and structured sleep history 
 
Actigraphy 
Global functioning and 
quality of life 
 
BASC-3 PRQ 
 
PGI scales 
 
Pediatric Quality of Life 
Inventory 
 
Caregiver top 3 concerns 
visual analog scale 
 
Vineland Adaptive 
Behavior Scale 
 
CGI scales 
 
Cognitive measures 
 
 
 
KiTAP 
 
RBANS 
 
ERP 
Abbreviations: ABC-C, Aberrant Behavior Checklist-Community; ADAMS, Anxiety, Depression, and Mood 
Scale; BASC-3 PRQ, Behavior Assessment System for Children, 3rd Edition Parenting Relationship 
Questionnaire; CGI, clinical global impressions; ERP, event related potential; KiTAP, Test of Attentional 
Performance for Children; LAR, legally acceptable representative; PGI, parent global impressions; 
RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; RBS-R, Repetitive 
Behavior Scale-Revised.  
 
 
6.3.1 
Caregiver Assessments 
6.3.1.1 
Aberrant Behavior Checklist-Community 
The Aberrant Behavior Checklist-Community (ABC-C) is a 58-item questionnaire completed 
by the LAR/caregiver that assesses a wide range of behaviors, including irritability, 
lethargy/social withdrawal, inappropriate speech, hyperactivity, stereotypic behavior, and 
social avoidance. Each item is rated on a scale of 0 to 3 (“not at all a problem” to “the 
problem is severe in degree”). The ABC-C will be scored 2 ways: according to the original 
method used to assess a population with a variety of disabilities (Aman et al 1985) and 
according to a method adapted for FXS that has a 6-factor structure (Sansone et al 2012). In 
the 6-factor method, 1 factor is unchanged from the original scoring (inappropriate speech); 4 


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factors are modified (irritability, hyperactivity, lethargy/withdrawal, and stereotypy); and 1 
new factor (social/avoidance) has been added. 
 
6.3.1.2 
Anxiety, Depression, and Mood Scales 
The Anxiety, Depression, and Mood Scales (ADAMS) is a caregiver-completed report that 
screens comprehensively for anxiety and depression in persons with intellectual disability 
and consists of 28 items grouped into 5 subscales that assess the frequency and severity of 
manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, and 
obsessive behavior (Esbensen et al 2003). 
 
6.3.1.3 
Repetitive Behavior Scale-Revised 
The Repetitive Behavior Scale-Revised (RBS-R) is a caregiver-completed, 43-item 
questionnaire assessing a variety of repetitive behaviors with 6 behavior subscales: 
stereotyped, ritualistic, self-injurious, compulsive, restricted, and sameness (Bodfish et al 
2000). 
 
6.3.1.4 
Conners 3rd Edition 
The Conners 3rd Edition (Conners 3; North Tonawanda Multi-Health System, North 
Tonawanda, NY) is designed to assess attention deficit hyperactivity disorder, and it will be 
used to collect LAR/caregiver observations of subject behavior. The assessment of behavior 
in neurodevelopmental disorders, such as FXS, frequently relies upon proxy report. The long 
form of Conners 3 is needed to assess inconsistency (reporter reliability) and will be 
administered at Screening only. The short form of Conners 3 will be administered as an 
outcome assessment at the baseline, Week 2, Week 6, EOT, and EOS visits. 
 
6.3.1.5 
Short Sensory Profile-2 
The Short Sensory Profile-2 is a caregiver questionnaire to evaluate a subject’s sensory 
processing patterns in the context of home, school, and community-based activities 
(PsychCorp, San Antonio, TX). 
 
6.3.1.6 
Children’s Sleep Habits Questionnaire 
The Children’s Sleep Habits Questionnaire (CSHQ) is a caregiver-completed assessment of 
sleep behaviors in children and adolescents (Owens et al 2000). The abbreviated version of 


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this questionnaire includes 33 items that assesses sleep habits and possible difficulties with 
sleep. The CSHQ should take 5 to 10 minutes to complete. 
 
6.3.1.7 
Sleep Diary 
A paper 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 7.3.1. The sleep diary 
will be completed each day during the 7 days immediately preceding each clinic visit after 
screening. The LAR/caregiver will continue to complete a sleep diary for a subject who is 
unable to tolerate wearing an actigraph (Section 6.3.3.1). 
 
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. Sleep diaries 
will be collected at each clinic visit, starting with the baseline visit (Table 6-1). 
 
6.3.1.8 
Behavior Assessment System for Children, 3rd Edition 
The Behavior Assessment System for Children, 3rd Edition, Parenting Relationship 
Questionnaire (BASC-3 PRQ) provides information on the relationship between a caregiver 
and a child across multiple dimensions (Pearson, New York, NY). It yields the following 
subscale scores: attachment, communication, discipline practices, involvement, parent 
confidence, satisfaction with school, and relation frustration. The questionnaire is written at a 
third grade level and also calculates a number of response validity scores, such as 
consistency and response pattern, to detect careless or exaggerated responding. It includes 
normative samples for both female and male raters that are closely matched to the US Census 
population estimates. 
 
6.3.1.9 
Parent Global Impressions Scales 
The Parent Global Impressions-Severity (PGI-S) scale will be completed by the 
LAR/caregiver to assess the severity of symptoms, and the Parent Global 
Impressions-Improvement (PGI-I) scale will be used by the LAR/caregiver to assess 
improvement from baseline. The PGI-S has been adapted to capture specific characteristics 
commonly present in the FXS population. 


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6.3.1.10 
Pediatric Quality of Life Inventory 
The Pediatric Quality of Life Inventory (PedsQL) generic core scales and Multidimensional 
Fatigue Scale will be administered in this study (Varni et al 2004). The generic core scales 
include 23 items covering the domains of physical, emotional, social, and school functioning. 
The Multidimensional Fatigue Scale contains 18 items measuring general fatigue, sleep/rest 
fatigue, and cognitive fatigue. 
 
6.3.2 
Clinician Assessments 
6.3.2.1 
Structured Sleep History Form 
On the initial screening visit, the clinician will complete parts A, B, and C of the structured 
sleep history form by interviewing the LAR/caregiver. The sleep history form is used by the 
clinician as a source document for completion of the Pediatric Sleep Clinical Global 
Impressions (Pediatric Sleep CGI) scales (Section 6.3.2.2). On all subsequent clinic visits 
starting with baseline, the clinician will complete only part A of the structured sleep history 
form. Part D of the structured sleep history form will not be used for this study. 
 
6.3.2.2 
Pediatric Sleep Clinical Global Impressions Scales 
The Pediatric Sleep CGI scales were recently developed to measure pediatric insomnia in 
autism spectrum disorder and have been validated against the CSHQ and actigraphy (Malow 
et al 2016). The clinician will interview the LAR/caregiver for each subject to complete the 
structured sleep history form (Section 6.3.2.1) as an aid to the clinician completing the 
Pediatric Sleep CGI-Severity and Pediatric Sleep CGI-Improvement scales as scheduled 
(Table 6-1). Questions include the subject's ability to fall asleep and remain sleeping 
independently (ie, apart from LAR/caregivers); bedtime resistance; sleep onset delay; night 
awakening; LAR/caregiver satisfaction with their child's current sleep patterns; family 
functioning, as affected by their child's current sleep patterns; and clinician's overall concern 
with the child's sleep. 
 
6.3.2.3 
Caregiver Top 3 Concerns Visual Analog Scale 
In Part 1 of the visual analog scale (VAS), LARs/caregivers will generate their top 3 concerns 
for the subject. The investigator will then map each LAR/caregiver-generated concern onto 
one FXS-specific domain (e.g. communication, activities of daily living, anxiety) to which 
each behavior or symptom applies. Part 2 of VAS will be used to rate FXS-specific domains, 


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including speech and communication, socialization, and cognition. The investigator will ask the 
LAR/caregiver to rate the behaviors in both Part 1 and 2, using a 10-cm VAS, with the 
descriptive anchors of “worst ever” and “best ever.”. 
 
6.3.2.4 
Vineland Adaptive Behavior Scale 
The Vineland Adaptive Behavior Scale, 3rd Edition (VABS-3) caregiver interview form will 
be used to evaluate communication, socialization, and daily living skills of subjects to assess 
their overall adaptive functioning (PsychCorp, San Antonio, TX). This assessment is an 
interview of the caregiver by a trained qualified rater. 
 
6.3.2.5 
Clinical Global Impressions Scales 
The CGI-S scale will be used by the investigator to assess the severity of symptoms, and the 
CGI-I scale will be used by investigators to assess improvement from baseline. The CGI-S 
has been adapted to capture specific characteristics commonly present in the FXS population. 
Both CGI-S and CGI-I will be conducted by a clinician with experience in FXS. 
 
6.3.3 
Direct Subject Assessments 
6.3.3.1 
Actigraphy 
Actigraphy is a noninvasive method of monitoring human rest/activity cycles. A small 
actigraph unit is worn to measure daytime and sleep activity. The actigraph unit stores motion 
data by clock time, and the data must be uploaded to an actigraphy database for analysis. 
 
Each subject will be provided a wearable actigraph unit (Actiwatch; Philips Respironics Inc, 
Murrysville, PA), preferably to be worn on the nondominant wrist. If the subject is not able to 
tolerate the Actiwatch on his wrist, he may wear it on his ankle. The Actiwatch can be 
attached with a hospital band if that makes it more acceptable for the subject. Once a body 
location is selected for attachment of the Actiwatch, every effort should be made to keep the 
location the same throughout the study. Severe sensory sensitivities exist in the study 
population, and it is anticipated that some subjects will not be able to tolerate wearing the 
device. Therefore, if a subject is not able to tolerate the Actiwatch and/or comply with the 
Actiwatch guidelines, he may continue to participate in the study. The Actiwatch will be 
worn during the 7 days immediately preceding each clinic visit after screening. It should be 


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worn continuously throughout the day and night for 7 consecutive days. The actigraphy data 
(Section 7.3.3) will be compared to the sleep diary data. 
 
6.3.3.2 
Test of Attentional Performance for Children 
The KiTAP is an automated computer-based assessment of attentional performance 
developed and normed for a pediatric population. The KiTAP is suitable for assessment of 
function in individuals of various ages, including children, adolescents, and adults, with FXS 
(Knox et al 2012). The task displays an “enchanted castle” animation and measures 8 aspects 
of attention: alertness, distractibility, divided attention, flexibility, go/no-go, sustained 
attention, vigilance, and visual scanning. 
 
6.3.3.3 
Repeatable Battery for the Assessment of Neuropsychological 
Status 
The RBANS provides a brief individually administered battery to assess cognitive function in 
individuals 12 years of age and older (Randolph et al 1998). The full battery consists of 
12 subtests to assess immediate memory, visuospatial abilities, language, attention, and 
delayed memory. In this study, 6 subtests of the RBANS will be used: list learning 
(immediate memory), list recall (delayed memory), list recognition (delayed memory index), 
story memory (immediate memory index), story recall (delayed memory index), and picture 
naming (language index). Each subtest can be administered in 5 minutes or less. 
 
6.3.3.4 
 
Electroencephalogram (EEG) recordings will be used to characterize resting EEG and ERP,  
and to assess treatment response and associated changes in cortical activity (Ethridge et al 
 
2016). Subjects will passively listen to 150 pairs (S1, S2) of 5-msec broadband noise bursts  
(65 dB) separated by an inter-stimulus interval of 500 msec. Inter-trial intervals will be 4000 
msec (average), for a total task duration of 11.25 minutes. Data from an  
electroencephalogram will be acquired continuously at a 1000 Hz sampling rate, and will be 
filtered online at 0.1 to 100 Hz, amplified (12,500×), and digitized (1000 Hz). Participants  
will view a standard silent movie of their choice during electroencephalogram recording. If  
the participant in unable to cooperate for the ERP testing, he will not be withdrawn from the 
study. Sites will be strongly recommended to conduct EEG/ERP assessments (if applicable  
based on EEG/ERP feasibility and completed consent).  
Event Related Potential 


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Subject participation in exploratory laboratory assessments is based on completion of 
separate, optional informed consents. 
6.4.1 
Metabolomic Biomarkers 
A minimum of 4 mL of blood will be drawn (1 green-top sodium heparin tube) for the 
purpose of identifying metabolomic biomarkers in plasma whose levels are associated with 
plasma levels of OV101, clinical presentation of FXS, or treatment response. Separated 
plasma will be subjected to liquid chromatography/high resolution mass spectrometry for 
metabolomic analyses, which will be compared to those from samples acquired from a 
biorepository from age-matched typically developing subjects to identify metabolomic 
biomarkers whose levels are associated with FXS. 
6.4.2 
Cheek Microbiome Assessments 
Cheek swabs will be obtained from each subject for purification of DNA and library 
preparation. Low-pass DNA sequencing will be used to identify secondary pathogenic 
of bacterial species present across the course of the study. Characterization of subject 
microbiomes will be performed with the goal of identifying microbiome species whose levels 
are associated with FXS clinical presentation or treatment response to OV101. Samples 
acquired from a biorepository from age-matched typically developing subjects will be used 
for comparison to identify species whose levels are associated with FXS. 
Data generation and analysis will be conducted by Gencove Inc (New York, NY), and the 
results may be reported separately. 
6.5 
Plasma OV101 Concentrations 
Blood for determining plasma OV101 concentrations will be drawn at each specified clinic 
visit (Table 6-1) 0.5 to 0.75 hours and 3 to 4 hours after administration of the morning dose 
in the clinic. 
Plasma OV101 concentration data obtained in this study may be combined with data from 
prior studies to perform population PK and PK-PD analyses and to evaluate the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Laboratory Assessments 
6.4 


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reported separately from the clinical study report (CSR) for this study. 
 
 
 
 
 
6.6 
Safety and Tolerability Assessments 
All subjects who receive study drug will be evaluated for study drug safety and tolerability. 
Assessments will include the frequency and severity of treatment-emergent AEs (TEAEs) 
and SAEs (including TEAEs leading to discontinuation), standardized clinical assessment of 
suicidality, clinical laboratory evaluations, and vital sign measurements. Safety and 
tolerability assessments will be conducted according to the schedule presented in Table 6-1. 
 
6.6.1 
Adverse Events 
6.6.1.1 
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 their clinical significance. 
 
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 randomization if any symptoms develop. 
 
A TEAE is defined as any event not present before exposure to study drug or any event 
already present that worsens in either intensity or frequency after exposure to study drug. 
 
6.6.1.2 
Serious Adverse Events 
An SAE is defined as any event that meets one of the following criteria: 
 
 Results in death 
 Is immediately life threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity not consistent with baseline 
level 
 Is a congenital anomaly/birth defect 
exposure-response of OV101 in individuals with FXS. The results of these analyses will be 


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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. 
 
6.6.1.3 
Eliciting and Documenting Adverse Events 
Adverse events will be assessed beginning at enrollment (date of signed informed consent) 
and up to 30 days after the last dose of study drug, and must be followed until resolution or 
for 30 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. 
 
At every clinic visit after informed consent and at all phone visits (Table 6-1), subjects 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 (eg, laboratory values, 
physical examination findings) or identified from the review of other documents (eg, 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. 
 
6.6.1.4 
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 


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Ovid/Sciformix 
Ovid/Sciformix 
Ovid/Sciformix 
number) 
 Event term (diagnosis, not symptoms) 
 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 
 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 that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
 
6.6.1.5 
Reporting Serious Adverse Events 
Investigators and other study center staff must immediately (ie, within 1 business day) inform 
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 must be faxed to the following number. 
 



Any AE that meets SAE criteria (Section 6.6.1.2) must be entered into the EDC system 
immediately (ie, within 1 business day) after site personnel first learn about the event. Once 
the qualifying SAE data are entered, 
will be notified by an email alert, which 
will contain high-level safety information. Additional safety information will be obtained 
from the EDC system via applicable eCRF pages. If the EDC system is not available, the site 
should send a completed, manual, paper SAE report form to 
by fax: 
Safety Hotline: 1-800-403-6981 (note: this is a combined phone and fax toll-free 


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Inc. 2017).


When the EDC system is again available, the site must enter all applicable information into 
the EDC system. All supporting source information concerning the SAE (eg, hospital 
records) should be provided by fax.  
 
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 a Sciformix safety specialist, or the site urgently 
needs to report an SAE or make 
used: 
 

aware of an SAE, the safety hotline should be 
 
If a site makes an initial report of an SAE by the safety hotline, the site must subsequently 
enter all applicable information into the EDC system immediately thereafter. 
 
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. 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 (ie, the subject or health care practitioner is unable to 
provide additional information or the subject is lost to follow-up). Serious AEs that occur 
more than 30 days after the last dose of study drug do not need to be reported unless the 
investigator considers them related to study drug. 
 
6.6.1.6 
Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate all suspected unexpected serious adverse reactions 
(SUSARs) and nonserious AEs of special interest against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to investigators, IRBs, 
and applicable health authorities, based on applicable legislation. 
 
To determine the reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the gaboxadol investigator’s brochure (Ovid Therapeutics 
Safety Hotline: 1-800-403-6981 
Sciformix 
Safety Fax Line: 1-800-403-6981 


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The sponsor will compare the severity of each suspected unexpected serious adverse reaction 
and the cumulative event frequency reported for the study with the severity and frequency 
reported in the investigator’s brochure. 
 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed. 
 
6.6.1.7 
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: 
 
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 the onset and duration of each episode. 
 
6.6.1.8 
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 test article 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. 


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Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, ie, 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. 
 
 
6.6.1.9 
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 to be stable. 
 
6.6.2 
Other Safety Assessments 
Safety assessments other than AEs (Section 6.6.1) will include standardized clinical 
assessment of suicidality (Section 6.8), clinical laboratory evaluations (Section 6.9), and vital 
sign measurements. 
 
6.6.2.1 
Vital Sign Measurements 
Vital sign measurements will include weight, blood pressure, heart rate, and temperature. 
Measurements of blood pressure, heart rate, and temperature should be attempted after the 
subject has been resting in a supine or sitting position for at least 10 minutes. 
 
6.7 
Monitoring Committees 
An Internal Monitoring Committee and Scientific Oversight Committee agreement charter 
will document the roles, responsibilities, scope of activities, communication pathway, and 
time of meetings. 


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6.7.1 
Internal Monitoring Committee 
The Internal Monitoring Committee is a committee that will review unblinded safety and 
efficacy data when 30 evaluable subjects have completed the EOT visit. It will consist of 
responsible representatives from Ovid clinical science, clinical pharmacology, statistics, drug 
safety, and statistical programming. 
 
6.7.2 
Scientific Oversight Committee 
The Scientific Oversight Committee will consist of at least 3 external, independent, non-Ovid 
experts responsible for monitoring the safety data to ensure that the study does not pose 
unacceptable risks to the subjects. 
 
6.8 
Clinical Assessment of Suicidality 
In accordance with the schedule in Table 6-1, the investigator will ask the subject’s 
LAR/caregiver the following questions (and record the answers in the eCRF): 
 
1. Suicidal ideation: Has the subject wished he were dead or wished he could go to sleep 
and not wake up? 
 
2. Suicidal behavior: Has the subject made a suicide attempt? Has the subject done 
anything to harm himself? 
 
3. Self-injurious behavior: Has the subject engaged in nonsuicidal self-injurious 
behavior? 
 
If the investigator determines that any of these questions can be asked directly to the subject 
based on his ability to understand and respond to the questions, then those questions should 
be directed to the subject. If the answer to any of these 3 questions is “yes,” then the 
investigator will further evaluate the suicidal risk of the subject. 
 
6.9 
Laboratory Analyses 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), including 
those that worsen from baseline, that are considered to be clinically significant in the medical 
and scientific judgment of the investigator are to be recorded as AEs or SAEs. 


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OV101 (PK assessment): Blood samples will be collected for determination of plasma 
concentrations of OV101. 
Details concerning the collection, processing, and handling of cheek swabs for microbiome 
assessments can be found in the PPD Central Laboratory manual. 
The following clinical analytes will be assessed: 
 
Hematology (safety assessment): 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 (safety assessment): 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; phosphate; potassium; alanine aminotransferase; aspartate 
aminotransferase; lactate dehydrogenase; sodium; chloride; bilirubin (total, direct); total 
protein; uric acid; and creatine phosphokinase. 
 
Urinalysis (safety assessment): macroscopic (pH, specific gravity, glucose, protein, ketones, 
nitrates, blood) and microscopic, reported only if present (red blood cells/high-power field, 
white blood cells/high-power field, casts, epithelial cells, crystals, granulation). 
 
 
 
6.10 Sample Collections 
Blood and urine 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 Section 6.1 and 
the investigator’s study manual, according to the schedule of activities (Table 6-1). Samples 
for hematology, clinical chemistry, or urinalysis will be used only for the evaluation of safety 
and tolerability. 
 
 


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OV101 plasma concentrations, and (optionally) determination of metabolomic biomarkers. 
Blood samples will be collected for clinical laboratory safety assessments, 
 
The maximum volume of blood to be collected per subject over the course of the study is 
estimated to be less than 140 mL. 
determination of 


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7 
Statistical and Analytical Plan 
7.1 
Primary Safety Endpoints 
Treatment-emergent AEs, treatment-related TEAEs, TEAEs leading to study discontinuation, 
and SAEs will be evaluated as primary safety endpoints. 
 
7.2 
Secondary Efficacy Endpoints 
The efficacy parameters of the continuous secondary endpoints will be the mean changes 
from baseline in ABC-C total and subscale scores; in ABC-C factor score for FXS; in the 
ADAMS subscale scores; in the RBS-R total and subscale scores; in Conners 3 subscale 
scores; in the Short Sensory Profile-2 total and subscale scores; and in the CGI-S and CGI-I 
scores. 
 
7.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints below are not listed in order of importance. 
 
7.3.1 
Caregiver-Completed Endpoints 
 Change from baseline in the BASC-3 PRQ subscale scores 
 
 Change from baseline in PGI-S and PGI-I scores 
 
 Change from baseline in PedsQL total and subscale scores 
 
 Change from baseline in the CHSQ total and subscale scores 
 
 Change from baseline in sleep diary parameters, including how long it took the 
subject to fall asleep (sleep onset latency [SOL]), the amount of time the subject was 
awake during the night (WASO), the total amount of sleep obtained (total sleep time 
[TST]), and daytime sleepiness, defined as duration of napping in the daytime. 
 
7.3.2 
Clinician-Completed Endpoints 
 Change from baseline in top 3 concerns visual analog scale 
 
 Change from baseline in the VABS-3 overall composite and subscale scores 


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7.4 
Other Exploratory Endpoints 
Mean change from baseline in ERP response 
Levels of plasma OV101 concentrations at sampling time points 
Changes from baseline in subject microbiomes 
Changes from baseline in biomarkers 
 Change from baseline in Pediatric Sleep CGI-Severity and Pediatric Sleep 
CGI-Improvement scores 
 
7.3.3 
Direct Subject Assessment Endpoints 
 Actigraphy parameters for sleep, including SOL, WASO, sleep fragmentation, 
number of nocturnal awakenings, TST, sleep efficiency, and daily activity level. 
 
 Mean change from baseline in KiTAP subtest scores 
  
 Mean change from baseline in RBANS subtest scores 
 
 
 
 
 
 
7.5 
Sample Size Calculations 
A sufficient number of subjects (36 estimated) will be enrolled to ensure that 30 evaluable 
subjects complete 12 weeks of treatment. Subjects will be randomly assigned to the 3 OV101 
total daily dosing regimens in a 1:1:1 ratio, stratified by age group (adolescents/adults), with 
a target ratio of 1:1 between adolescents and adults. 
 
The main emphasis in reporting the data will be on descriptive statistics and estimation with 
95% CIs. 
 
For the objective of estimating the overall subject incidence of TEAEs (for the 3 OV101 total 
daily dose arms combined), the precision varies with true incidence, eg, a true incidence of 
20% would be estimated with a 13.9% precision (half-width of the 2-sided 95% CI, assuming 
N = 30). Table 7-1 contains the estimated precision for different incidence rates, using the 
Wilson method of calculating a confidence interval for a binomial proportion. 


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Table 7-1 
Incidence Rates and Corresponding Precision 
 
True TEAE Incidence Rate 
10% 
13.3% 
20% 
23.3% 
30% 
Expected n with a TEAE 
(N=30) 
3 
4 
6 
7 
9 
Expected proportion, p 
0.100 
0.133 
0.200 
0.233 
0.300 
95% CI 
(3.5%, 25.6%) (5.3%, 29.7%) (9.5%, 37.3%) (11.8%, 40.9%) (16.7%, 47.9%) 
Precision (half-width of CI) 
11.1% 
12.2% 
13.9% 
14.6% 
15.6% 
Note: All CIs are 2-sided and 95% CIs are calculated using Wilson’s method. 
Abbreviations: n, number of subjects observed; N, total number of evaluable subjects in the study (all treatment 
groups); TEAE, treatment-emergent adverse event. 
 
 
7.6 
Analysis Sets 
The following analysis sets are defined: 
 
Randomized Analysis Set: The randomized analysis set will consist of all randomly assigned 
subjects. 
 
Full-Analysis Set (FAS): The FAS will consist of all randomly assigned subjects who receive 
at least 1 dose of study drug and have at least 1 postbaseline efficacy assessment. Following 
the intent-to-treat principle, subjects will be analyzed according to the treatment they are 
assigned to at randomization, regardless of compliance or any deviations from the study 
protocol. 
 
Modified Full-Analysis Set (mFAS): The mFAS will consist of all subjects in FAS, excluding 
data after a subject discontinues treatment or commences treatment with a prohibited 
medication. 
 
Safety Set: The safety set will consist of all subjects who receive at least 1 dose of study 
drug. All analyses using the safety set will group subjects according to treatment actually 
received. 
 
The randomized analysis set will be used for summaries of subject disposition, 
demographics, and other baseline characteristics. All safety evaluations will be carried out on 
the safety set. All efficacy evaluations will be carried out on the FAS. The mFAS may be 
used for exploratory modelling of selected efficacy variables, in addition to the FAS. 


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7.7 
Description of Subgroups to be Analyzed 
Scatter plots of data will distinguish the age groups (adolescent/adult) with different symbols 
to allow visual assessment of the consistency of data between these groupings. In addition, 
listings of all data will identify the age group of each subject. In the case of an endpoint that 
is further analyzed through the Mixed Model with Repeated Measures (MMRM; 
Section 7.8.5) and for which differences between age groups are apparent, an age by time by 
treatment interaction may be included in the model in order to present estimates for each age 
group separately (in addition to overall). 
 
Additional subgroup statistical analyses may be performed, as detailed in a separate 
statistical analysis plan. 
 
7.8 
Statistical Analysis Methodology 
The detailed methodology for the summary and statistical analyses of the data collected in 
this study will be documented in a separate statistical analysis plan. This document may 
modify the plans outlined in the protocol; however, any major modifications of the endpoint 
definitions and/or their analyses will also be reflected in a protocol amendment. 
 
All statistical analyses will be performed using SAS software Version 9.3 or higher. 
 
Descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum) will 
be presented for continuous variables and their changes from baseline. In addition, 95% CIs 
for the mean change from baseline will be provided for continuous variables. Graphical 
displays will be utilized to investigate trends over time and dose and the relationship between 
certain variables and differences between age groups. 
 
Ordinal variables with sufficient numerical categories (eg, 7-point scales of PGI-S and 
CGI-S) and subscale total scores from questionnaires will be treated as continuous variables. 
 
Categorical (not treated as continuous) endpoints (including AE incidence and binary 
endpoints) will be summarized by frequency and percentage. Frequencies and percentages 
will be presented for the shifts in these categories (eg, low to normal, low to high, high to 
low) from baseline to each post-treatment assessment time point for scales with categorical 
variables. If there are missing values, the number missing will be presented (as a category), 
but without a percentage. All data collected will be included in by-subject data listings. 


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7.8.1 
Safety Analyses 
All safety analysis will be performed on the safety set. 
 
All AEs will be coded using MedDRA and will be classified by MedDRA system organ class 
(SOC) and preferred term (PT). 
 
The number and percentage of subjects who experience at least 1 TEAE and the number and 
percentage of subjects who experience at least 1 TEAE within each specific SOC and PT will 
be presented by daily dosing regimen and overall. The number of TEAEs (event incidence) 
will also be summarized within each SOC and PT. 
 
The Wilson 95% CIs will be displayed for the proportion of subjects experiencing TEAEs as 
a total across the 3 dosing regimens. 
 
Treatment-related AEs will be identified as those that are at least possibly related to 
investigational product based on the investigator’s assessment. The number and percentage 
of subjects reporting SAEs, TEAEs, and AEs leading to study continuation will also be 
summarized by MedDRA SOC and PT. 
 
For each SOC and each PT, a subject will be counted only once for subject-incidence 
tabulations. For summaries of severe or treatment-related AEs, for a given subject, the 
highest severity or relationship for a specific PT will be considered. Adverse events with 
missing start dates will be considered treatment emergent. 
 
Number and percentage of deaths will be tabulated by primary SOC and PT. 
 
Descriptive statistics for laboratory values and vital sign measurements at each time point 
will be summarized. Clinically significant laboratory values may be tabulated. 
 
Shift tables for laboratory parameters will be presented to show the change of normality from 
baseline to each postbaseline visit. For each continuous laboratory parameter, results will be 
categorized as low, normal, or high based on the laboratory reference ranges. Frequencies 
and percentages will be presented for the shifts in these categories (eg, low to normal, low to 
high, high to low) from baseline to each post-treatment assessment time point. 


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7.8.4 
Analyses of Other Exploratory Endpoints 
Key outcomes for ERP will be changes in amplitude and latency of N1 and P2 waveforms as 
well as changes in percent habituation of N1 amplitude. Analyses across the entire waveform 
will be more exploratory, examining any unanticipated effects of treatment. 
Tables and graphical displays (eg, scatter plots of baseline versus worst postbaseline values) 
of key safety parameters may be generated to better understand the study drug safety profile. 
 
Shift tables for Clinical Assessment of Suicidality data will be presented to show the change 
in answers (yes/no) from baseline to postbaseline visits. 
 
Abnormal findings in physical examinations will be listed. 
 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. A table summarizing concomitant medications and a by-subject listing of 
concomitant medications will include all medications taken during the study regardless of the 
timing for the start of the medication. 
 
7.8.2 
Analysis of Secondary Efficacy Endpoints 
Descriptive statistics for efficacy variables at each time point will be displayed by daily 
dosing regimen and overall. Post-hoc exploratory modelling may be conducted on selected 
variables (Section 7.8.5) using the FAS (and mFAS, as required). 
 
7.8.3 
Analyses of Exploratory Endpoints 
Exploratory endpoints will be analyzed using the same methods as used for the secondary 
efficacy endpoints. Post-hoc exploratory modelling may be conducted on selected variables 
(Section 7.8.5) using the FAS (and mFAS as required).  
 
 
 
 
 
 
Individual plasma OV101 concentrations will be listed, plotted, and summarized in the same 
way as other continuous endpoints (number of subjects, mean, SD, median, minimum, and  
maximum). The plasma OV101 concentrations will be used in combination with data from 
other studies to inform population PK and PK-PD analyses and to evaluate the exposure-  
response of OV101 in individuals with FXS.  


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generated to better understand the OV101 PK-PD profile. 
The results for biomarker samples (plasma and cheek swabs) and the analysis of the 
combined effect of biomarker samples and treatment with OV101 will be reported in a 
document separate from the CSR. 
 
 
 
 
 
 
 
7.8.5 
Exploratory Modelling 
Post-hoc exploratory modelling may be conducted on selected variables using an MMRM to 
further investigate any trends evident in the descriptive statistics and to inform a future study. 
 
In case of post-hoc exploratory modelling, the MMRM analysis will be performed on the 
change from baseline in the response variable with baseline as a covariate and fixed effects 
for daily dosing regimen, week, age group and week by daily dosing regimen interaction. An 
unstructured covariance structure will be assumed. From this model, the least squares mean 
change from baseline and the corresponding 95% CI will be presented for each daily dosing 
regimen and the total (all regimens) at each week. The least squares mean difference and the 
corresponding 95% CI will be presented for each pairwise comparison between the 3 daily 
dosing regimens at each week. 
 
The least squares mean changes from baseline and corresponding 95% CIs will be plotted at 
each time point by daily dosing regimens. 
 
In the case of a statistically significant age group main effect (P<0.05) in the MMRM or age 
effects deemed evident in descriptive statistics, the mean changes with 95% CI described 
above will be estimated for each age group separately as well as overall; this will be achieved 
by inclusion of an additional term (age by week by daily dosing regimen interaction) in the 
MMRM. In this case, these additional estimates and 95% CI will be tabulated and plotted. 
 
7.8.6 
Other Analyses 
7.8.6.1 
Demographics and Other Baseline Characteristics 
Demographic and background information variables and subject disposition will be listed by 
subject and summarized using frequency distributions for categorical variables and 
descriptive statistics (ie, number of subjects, mean, SD, minimum, median, and maximum) 
Graphical displays (eg, scatter plots of PK concentrations versus PD response) may be 


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for continuous variables. Relevant medical history/current medical conditions will be 
summarized by SOC and PT of MedDRA. 
 
Background information will consist of data collected in the molecular FXS testing, clinical 
assessment of FXS, DSM-5 criteria for autism spectrum disorder, and IQ. 
 
The above analyses will be performed based on the randomized analysis set. 
 
7.8.6.2 
Drug Treatments 
7.8.6.2.1 
Study Drug 
Using the safety set, duration (days) of exposure to study drug and treatment compliance will 
be listed by subject and summarized descriptively by daily dosing regimen. Frequency and 
percentages for subject disposition and reasons for discontinuation of study drug will be 
presented. 
 
7.8.6.2.2 
Prior and Concomitant Medications 
Using the randomized analysis set, prior and concomitant medications will be listed by 
subject and summarized descriptively. 
 
7.8.7 
Interim Analyses 
No interim statistical analysis will be performed. Periodic interim blinded review of safety 
data will be performed as part of routine pharmacovigilance activities. 


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8 
Data Quality Assurance 
This study will be conducted according to the risk and quality processes described in the 
relevant procedural documents. The quality management approach to be implemented in this 
study will be documented and will comply with International Council for Harmonisation 
(ICH) E6(R2) guidance on quality and risk management. 
 
Standard operating procedures are available for all activities relevant to the quality of this 
study. Designated personnel 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 trial. 
 
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 
sponsor policy. Such audits will require access to study records, documentation, and 
regulatory files. At all times, subject privacy will be of utmost importance and will be 
respected. Typically, sufficient notice will be given to the investigator to prepare for the visit. 
 
In the event of an audit or inspection, the investigator (and institution) must agree to grant the 
auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time 
and the time of their staff to discuss any findings or relevant issues. 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. 
 
Responsibility for the accuracy, completeness, and reliability of the study data presented to 
the sponsor lies with the investigator generating the data. 
 
8.1 
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 


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protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include documents including (but not 
restricted to) the following: laboratory reports, questionnaire results, sleep diaries, and 
computerized or otherwise automated assessments. 
 
Investigative site personnel will enter subject data into Medidata RAVE® (the eCRF EDC 
program). The analysis data sets will be a combination of these data and data from other 
sources (eg, 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, eg, removing errors and 
inconsistencies in the data. There will be 100% source data verification. 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. 
 
After database lock, each study site will receive a CDROM containing all of their 
site-specific eCRF data as entered into the EDC system for the study, including full 
discrepancy and audit history. Additionally, a CDROM copy of all of the study site’s data 
from the study will be created and sent to the sponsor for storage. PPD will maintain a 
duplicate CDROM 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 
Institutional Review Board(s) 
Federal regulations and ICH guidelines require that approval be obtained from an IRB before 
participation of human subjects in research studies. Before study onset, the protocol, 
informed consent and 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 LAR/caregiver must be approved by the IRB. Documentation of all IRB approvals 
and of IRB 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 approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, all approved 
materials, 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. The 
investigator must promptly supply the sponsor or its designee, the IRB, 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 US Title 21 CFR Part 50 shall be obtained 
from each adult competent subject (or from the LAR/caregiver of a minor or adult of 
diminished mental capacity, as applicable) before the subject enters the study or any unusual 
or nonroutine procedure that involves risk to the subject is performed. For minors or adults of 
diminished mental capacity, an assent document will be presented and assent 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 


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There will be separate optional consents and assents for metabolomic analysis as well as for 
cheek swab sampling and subsequent processing for microbiome analysis. Those subjects for 
whom optional consents are not provided will still be eligible for the main study. 
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 informed consent form (ICF) is 
revised during the course of the study, all active participating subjects and LAR/caregivers 
(as applicable) must sign the revised forms.  
 
 
 
 
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 
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 the IRB. 
 
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 course of the 
investigation 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. 


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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: 
 
 IRB 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 subinvestigator 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-approved informed consent, 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. 


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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 according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB 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 with a summary of the study’s 
outcome and the sponsor and regulatory authority(ies) with any reports required. 
 
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 
External Data Monitoring Committee 
There will not be an external data monitoring committee for this study. 
 
11.1.2 
Monitoring of the Study 
The medical monitor, as a representative of the sponsor, has the obligation to follow the study 
closely. 
 
The study monitor will visit the investigator and study site at periodic intervals, in addition to 
maintaining necessary telephone and letter contact. The study 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. 
 
11.1.3 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB 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.  
 
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. 


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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 
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 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 for review and approval, to the sponsor for agreement, and to 
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 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 of deviations in writing by the 
monitor. The IRB 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 his last visit 
(includes follow-up visit). 


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11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
CSRs are prepared and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). 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 clinical study reports. 
 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for 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 and their LAR/caregivers, as appropriate. The study results will be posted on 
publicly available clinical trial registers. 


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Varni JW, Sherman SA, Burwinkle TM, et al. The PedsQL™ Family Impact Module: 
preliminary reliability and validity. Health Qual Life Outcomes. 2004;2:55. 
 
Wheeler AC, Raspa M, Bishop E, et al. Aggression in fragile X syndrome. J Intellect Disabil 
Res. 2016;60(2):113-25. 
 
Whissell PD, Rosenzweig S, Lecker I, et al. γ-Aminobutyric acid type A receptors that 
contain the δ subunit promote memory and neurogenesis in the dentate gyrus. Ann Neurol. 
2013;74(4):611-21. 
 
Zhang J, Fang Z, Jud C, et al. Fragile X-related proteins regulate mammalian circadian 
behavioral rhythms. Am J Hum Genet. 2008;83(1):43-52. 


Ovid Therapeutics Inc. 
Protocol: OV101-17-001 Version 1.2 
OV101 
27 Mar 2019 
Page 105 
 
 
13 Appendix (Israel Site-Specific Instructions) 
The SB-5, which is to be conducted at screening, is not available in Hebrew. Therefore, for 
the site in Israel, alternative IQ assessments such as the Wechsler Intelligence Scale for 
Children (WISC), Wechsler Preschool and Primary Scale of Intelligence (WPPSI), or 
Kaufman Assessment Battery for Children (KABC) may be used. It is important that the 
alternative IQ test yields a full scale IQ (with nonverbal and verbal scores). For example, the 
Leiter International Performance Scale is a nonverbal intelligence test and therefore, would 
not be an appropriate substitute of the SB-5. 
 
An equivalent previously documented IQ measurement conducted within 3 years of the 
screening visit can be used to qualify the subject as having an IQ less than 75. 

SAP_001.pdf: 
Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
Jing Xu 
PPD 
929 North Front Street 
 
 
 
 
 
 
 
 
Ovid Therapeutics, Inc. 
 
OV101-17-001 
 
A Phase 2a, Randomized, Double-Blind, Parallel-Group, Proof-of-Concept Study 
Evaluating the Safety, Tolerability, and Efficacy of OV101 in Fragile X Syndrome 
 
06MAR2020 
 
Statistical Analysis Plan 
Version 3.0 
Prepared by: 
 
 
 
 
 
Senior Biostatistician II 
 
 
 
 
 
 
 
 
Wilmington, North Carolina 28401-3331 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
PPD 
Ovid Therapeutics, Inc. 
Ovid Therapeutics, Inc. 
 
Approved by 
 
 
 
 
Date:  
/ 
/ 
 
 
 
 
Senior Manager, Biostatistics 
 
 
 
Date:  
/ 
/ 
 
 
 
 
VP, Biostatistics and Data Management 
 
 
 
Date:  
/ 
/ 
 
 
 
 
VP, Clinical Development 
Mathews Adera, MD 
Ying Yan 
Yunbin Zhang 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
TABLE OF CONTENTS 
List of Abbreviations and Definition of Terms 
6 
1. 
INTRODUCTION 
9 
2. 
OBJECTIVES 
11 
2.1. 
Primary Objective 
11 
2.2. 
Secondary Objectives 
11 
2.3. 
Exploratory Objectives 
11 
3. 
INVESTIGATIONAL PLAN 
12 
3.1. 
Overall Study Design and Plan 
12 
3.2. 
Study Endpoints 
13 
3.2.1 Primary Safety Endpoints 
13 
3.2.2 Secondary Efficacy Endpoint 
14 
3.2.3 Exploratory Endpoints 
14 
3.2.3.1 Caregiver-Completed Endpoints 
14 
3.2.3.2 Clinician-Completed Endpoints 
14 
3.2.3.3 Direct Subject Assessment Endpoints 
14 
3.2.3.4 Other Exploratory Endpoints 
14 
3.3. 
Treatments 
15 
3.4. 
Dose Adjustment/Modification 
15 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
16 
4.1. 
Visits and Day Ranges 
17 
4.2. 
Sample Size 
17 
4.3. 
Stratification, Randomization, and Blinding 
18 
4.4. 
Analysis Set 
18 
5. 
SUBJECT DISPOSITIONS 
20 
5.1. 
Dispositions 
20 
5.2. 
Protocol Deviations 
20 
6. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
21 
6.1. 
Demographic 
21 
6.2. 
Baseline Characteristics 
21 
6.3. 
Medical History 
21 
6.3.1 General Medical History 
21 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
Cheek Microbiome Assessments 
Metabolomic Biomarkers 
Evoked Response Potential 
6.4. 
Inclusion and Exclusion Criteria 
21 
7. 
TREATMENTS AND MEDICATIONS 
22 
7.1. 
Prior and Concomitant Medications and Procedures 
22 
7.2. 
Study Treatments 
22 
7.2.1 Extent of Exposure 
22 
7.2.2 Treatment Compliance 
23 
8. 
EFFICACY ANALYSES 
24 
8.1. 
Secondary Efficacy Analysis 
24 
8.1.1 Aberrant Behavior Checklist-Community (ABC-C) 
24 
8.1.2 Anxiety, Depression, and Mood Scales (ADAMS) 
26 
8.1.3 Repetitive Behavior Scale-Revised (RBS-R) 
27 
8.1.4 Conner’s 3rd Edition 
28 
8.1.5 Short Sensory Profile-2 
29 
8.1.6 Clinical Global Impressions Scales 
30 
8.2. 
Exploratory Efficacy Analysis 
30 
8.2.1 Caregiver-Completed Endpoints 
30 
8.2.1.1 Behavior Assessment System for Children, 3rd Edition (BASC-3 PRQ) 
30 
8.2.1.2 Parent Global Impressions Scales 
32 
8.2.1.3 Pediatric Quality of Life Inventory 
33 
8.2.1.4 Children’s Sleep Habits Questionnaire 
34 
8.2.1.5 Sleep Diary 
34 
8.2.2 Clinician-Completed Endpoints 
37 
8.2.2.1 Caregiver Top 3 Concerns Visual Analog Scale 
37 
8.2.2.2 Vineland Adaptive Behavior Scale 
38 
8.2.2.3 Pediatric Sleep Clinical Global Impressions Scales 
39 
8.2.3 Direct Subject Assessment Endpoints 
40 
8.2.3.1 Actigraphy 
40 
8.2.3.2 Test of Attentional Performance for Children 
42 
8.2.3.3 Repeatable Battery for the Assessment of Neuropsychological Status 
43 
8.2.3.4 
44 
8.2.4 
45 
8.2. 5 
45 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
Pharmacokinetic Analysis 
8.3. 
45 
9. 
SAFETY ANALYSES 
46 
9.1. 
Adverse Events 
46 
9.1.1 Incidence of Adverse Events 
46 
9.1.2 Relationship of Adverse Events to Study Drug 
47 
9.1.3 Severity of TEAEs 
47 
9.1.4 Serious TEAEs 
47 
9.1.5 TEAEs Leading to Study Discontinuation 
47 
9.1.6 TEAEs with Outcome of Death 
47 
9.1.7 TEAEs with Seizure 
47 
9.2. 
Clinical Laboratory Evaluations 
48 
9.2.1 Hematology 
48 
9.2.2 Clinical Chemistry 
48 
9.2.3 Urinalysis 
49 
9.3. 
Vital Signs 
49 
9.4. 
Physical Examination 
49 
9.5. 
Clinical Assessment of Suicidality 
49 
10. 
INTERIM ANALYSIS 
50 
11. 
OTHER STATISTICAL ISSUES 
51 
11.1. Significance Levels 
51 
11.2. Handling of Missing Data 
51 
12. 
CHANGES COMPARED TO THE PROTOCOL 
53 
13. 
REFERENCES 
54 
14. 
APPENDICES 
56 
14.1. Imputation Algorithm for Partial and Missing Dates 
56 
14.2. Schedule of Study Procedures 
57 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation 
Definition 
ABC-C 
Aberrant Behavior Checklist-Community 
ADAMS 
Anxiety, Depression, and Mood Scales 
ADHD 
Attention Deficit Hyperactivity Disorder 
AE 
Adverse Event 
AM 
Morning dose only 
AS 
Angelman Syndrome 
ATC 
Anatomical Therapeutic Class 
BASC-3 PRQ 
Behaviour Assessment 
System for Children, 3rd 
Edition, Parenting 
Relationship Questionnaire 
BID 
Twice a Day 
CGI 
Clinical Global Impressions 
CGI-I 
Clinical Global Impressions-Improvement 
CGI-S 
Clinical Global Impressions-Severity 
CI 
Confidence Interval 
Conner’s 3 
Conner’s 3rd Edition 
CSHQ 
Children’s Sleep Habits Questionnaire 
CSR 
Clinical Study Report 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
EOS 
End of Study 
EOT 
End of Treatment  
ERP 
Evoked Resting Potential 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FXS 
Fragile X Syndrome 
GABA 
Gamma-aminobutyric Acid 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IQ 
Intelligence Quotient 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
KiTAP 
Test of Attentional Performance for Children 
KO 
Knockout 
LAR 
Legally Acceptable Representative 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mmHg 
Millimeter of mercury 
MMRM 
Mixed Model with Repeated Measures 
PD 
Pharmacodynamic(s) 
PedsQL 
Pediatric Quality of Life Inventory 
PGI-I 
Parent Global Impressions-Improvement 
PGI-S 
Parent Global Impressions-Severity 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
Q1 
1st Quartile 
Q3 
3rd Quartile 
QD 
Once a Day 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
RBS-R 
Repetitive Behavior Scale-Revised 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
 
SB-5 
Stanford-Binet-5 
SD 
Standard Deviation 
SI 
International System 
SOC 
System Organ Class 
SOL 
Sleep Onset Latency 
TEAE 
Treatment-Emergent Adverse Event 
TID 
Three Times a Day 
TST 
Total Sleep Time 
VABS-3 
Vineland Adaptive Behavior Scale, 3rd Edition 
WASO 
Wake Time After Sleep Onset 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
1. INTRODUCTION 
 
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, with 
a prevalence of 1 in 4000 males and 1 in 8000 females (Crawford et al 2001). It is also the 
most common known genetic cause of autism; approximately 25% to 30% of individuals with 
FXS meet the full diagnostic criteria for autism, and approximately 5% of children with autism 
carry the fragile X mutation (Hall et al 2008; Harris et al 2008). Males with FXS have moderate 
to severe intellectual disability, and females with FXS range from normal to moderate 
impairment (Hagerman et al 2010). 
 
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. The mechanism of action of OV101 is unique among GABAergic agents, 
including benzodiazepines, zolpidem and other zolpidem-like drugs, neurosteroids, and drugs 
that act on GABA metabolism or uptake. 
 
The use of OV101 for treatment of individuals with FXS is based on studies in a relevant 
mouse model of the disease, the Fmr1 knockout (KO) mouse, which lacks the fragile X mental 
retardation protein due to a disruption in its FMR1 gene. Fmr1 KO mice have decreased GABA 
synthesis, decreased presynaptic GABA release, and decreased extrasynaptic levels of GABA, 
resulting in decreased tonic inhibition. OV101 was shown to restore tonic inhibition in the 
amygdala, reduce sensory hypersensitivity and motor hyperactivity, and improve pre-pulse 
inhibition (signal to noise ratio) in Fmr1 KO mice. Cogram et al recently presented data that 
showed full normalization of abnormal repetitive, social, and anxiety-like behaviors with 
OV101 in another FXS KO mouse model, the Fmr1 KO2 mouse. Taken together, these data 
support the potential of OV101 to treat the core behavioral deficits noted in individuals with 
FXS. Importantly, the ability of OV101 to potentiate tonic inhibition is unlike any other 
GABAergic agent, including benzodiazepines, zolpidem, other zolpidem-like drugs, 
neurosteroids, and drugs that act on GABA metabolism or uptake. 
 
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. 
 
This Statistical Analysis Plan (SAP) describes the data-handling and statistical procedures to 
be used for the statistical analysis and reporting of efficacy and safety data collected under the 
Ovid Protocol OV101-17-001 Amendment #2 (March 27, 2019). The methods of analysis in 
this SAP expand on statistical considerations identified in the protocol; where considerations 
are substantially different, they will be identified as such in this document. This SAP has been 
developed and finalized prior to locking the clinical database for the primary analysis. Any 
additional analyses required to supplement the analyses specified in this SAP will be 
considered exploratory and will be identified in the Clinical Study Report (CSR). 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principals for Clinical Trials” and the most recent ICH-E3 Guideline entitled “Guidance for 
Industry: Structure and Content of Clinical Study Reports.” 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
2. OBJECTIVES 
 
2.1. Primary Objective 
 
 To evaluate the safety and tolerability of OV101 over 12 weeks of treatment across 
different daily dosing regimens in adolescent and adult male subjects with FXS. 
 
2.2. Secondary Objectives 
 
 To evaluate changes in behavior during 12 weeks of treatment with OV101 across different 
daily dosing regimens in adolescent and adult male subjects with FXS 
 
2.3. Exploratory Objectives 
 
 To evaluate changes in sleep, adaptive functioning, and quality of life across different daily 
dosing regimens of OV101 treatment over 12 weeks in adolescent and adult male subjects 
with FXS
To evaluate possible acute rebound phenomena (e.g., sleep disruption or behavioral 
problems) that occur following discontinuation of treatment with OV101 using outcome 
assessments administered at a follow-up visit 4 to 6 weeks after the end of treatment  
 To explore the relationships among plasma levels of OV101, metabolomic biomarkers, and 
treatment response 
 To explore the relationships among subjects’ microbiomes and clinical presentation of FXS  
or treatment response
 To explore the relationships between evoked resting potential (ERP) measurements and 
levels of OV101 or treatment response
 To explore the relationships among study endpoints (e.g., behavior, sleep), where 
appropriate
 To obtain plasma OV101 concentrations for use in combination with data from other 
studies to perform population PK and PK-pharmacodynamic (PD) analysis and to 
evaluate the exposure-response of OV101 in individuals with FXS


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
3. INVESTIGATIONAL PLAN 
 
3.1. Overall Study Design and Plan 
 
This is a Phase 2a, randomized, double-blind, parallel-group study to evaluate the safety, 
tolerability, and efficacy of OV101 administered daily as 3 different dosing regimens: 5 
mg/day (5 mg QD), 10 mg/day (5 mg BID), and 15 mg/day (5 mg TID) in adolescent and adult 
male subjects with FXS. Subjects with a clinically and molecularly confirmed diagnosis of 
FXS will be eligible for inclusion in the study (Section 4.1 of the protocol). The study will 
comprise a screening period of up to 3 weeks; a baseline visit on Day 1 for treatment 
randomization (enrollment), baseline assessments, and first dose of study drug; clinic visits for 
safety and efficacy assessments over a 12-week treatment period, including clinic visits at 
Week 2, Week 6, and Week 12 (end-of-treatment [EOT]); and an end-of-study (EOS) follow- 
up visit occurring any time between the ends of Week 16 and Week 18 (Figure 1). The schedule 
of study procedures is presented in Section 13.5. 
 
Figure 1 Study Schematic 
 
 
 
 
 
 
 
For each subject, after informed consent is obtained (Section 9.3 of the protocol), screening 
assessments will be completed within the 3 weeks preceding Baseline. At Baseline, subjects 
13 to 22 years old (inclusive) who meet all eligibility criteria (Section 4.1 of the protocol) will 
be enrolled on Day 1 in a 1:1 target ratio between adolescents (13 to17 years old, inclusive) 
and adults (18 to 22 years old, inclusive). A sufficient number of subjects will be enrolled to 
ensure that at least 30 evaluable subjects complete 12 weeks of treatment. 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
Subjects will be randomly assigned in a 1:1:1 ratio to 1 of 3 treatment groups (5 mg QD, 5 mg 
BID, and 5 mg TID), stratified by age group (adolescent/adult) to achieve balance among 
treatment arms. There is no placebo group in this study. All subjects will take study drug TID 
(morning, afternoon, and evening), OV101 in the morning and OV101 or placebo in the 
afternoon and evening throughout the treatment period (including Baseline), as described in 
Section 5.2 and Section 5.4.1 of the protocol. There will not be any dose adjustments permitted 
during the study. 
 
After random assignment at Baseline, subjects will receive the assigned package of blinded 
study treatment according to the treatment code for the first 6 weeks of treatment and will take 
their first dose of study drug at the clinic. They will receive another assigned package of 
study treatment at the Week 6 clinic visit. 
 
Each subject (assisted by a legally acceptable representative [LAR]/caregiver) will complete 
paper sleep diaries and wear actigraphs over the 7-day periods immediately preceding Baseline 
and the Week 2, Week 6, EOT, and EOS clinic visits. The Baseline, Week 2, Week 6, and EOT 
visits will be full-day clinic visits. 
 
For each subject, after informed consent is obtained, the maximum duration of individual 
subject participation will be 21 weeks. A subject will have completed the study when he 
completes the EOS visit. The end of the study is defined as the date when the last subject 
completes his last visit (includes follow-up visit). 
 
Safety information will be collected during phone calls at the end of Weeks 1, 4, 8, and 10 (on 
Days 8, 29, 57, and 71, respectively), in addition to during every clinic visit (screening, 
baseline, Week 2, Week 6, EOT, and EOS). At the investigator’s discretion, subjects may be 
evaluated at unscheduled clinic visits for reasons related to subject safety. At unscheduled 
visits, subjects will be queried about AEs, changes in concomitant medications, and suicidality, 
and safety laboratory assessments may be conducted. Periodic interim blinded review of safety 
data will be performed as part of routine pharmacovigilance activities. No interim statistical 
analysis is planned. 
 
3.2. Study Endpoints 
 
3.2.1 Primary Safety Endpoints 
 
Treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to 
study discontinuation, and serious adverse events (SAEs) will be evaluated as primary safety 
endpoints. 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
3.2.2 Secondary Efficacy Endpoint 
 
The efficacy parameters of the continuous secondary endpoints will be the mean changes from 
baseline in ABC-C total and subscale scores; in ABC-C factor score for FXS; in the ADAMS 
subscale scores; in the RBS-R total and subscale scores; in Conner’s 3 subscale scores; in the 
Short Sensory Profile-2 total and subscale scores; and in the CGI-S and CGI-I scores. 
 
3.2.3 Exploratory Endpoints 
 
The exploratory efficacy endpoints are not listed in order of importance. 
 
3.2.3.1 Caregiver-Completed Endpoints 
 
● 
Change from baseline in the BASC-3 PRQ subscale scores 
● 
Change from baseline in PGI-S and PGI-I scores 
● 
Change from baseline in PedsQL total and subscale scores 
● 
Change from baseline in the CHSQ total and subscale scores 
● 
Change from baseline in sleep diary parameters, including how long it took the subject to 
fall asleep (sleep onset latency [SOL]), the amount of time the subject was awake during 
the night (WASO), the total amount of sleep obtained (total sleep time [TST]), and daytime 
sleepiness, defined as duration of napping in the daytime. 
3.2.3.2 Clinician-Completed Endpoints 
 
● 
Change from baseline in top 3 concerns visual analog scale 
● 
Change from baseline in the VABS-3 overall composite and subscale scores 
● 
Change from baseline in Pediatric Sleep CGI-Severity and Pediatric Sleep CGI- 
Improvement scores 
 
3.2.3.3 Direct Subject Assessment Endpoints 
 
● 
Actigraphy parameters for sleep, including SOL, WASO, sleep fragmentation, number of 
nocturnal awakenings, TST, sleep efficiency, and daily activity level. 
● 
Mean change from baseline in KiTAP subtest scores 
● 
Mean change from baseline in RBANS subtest scores 
 
3.2.3.4 Other Exploratory Endpoints 
 
● 
Mean change from baseline in ERP response 
● 
Levels of plasma OV101 concentrations at sampling time points 
● 
Changes from baseline in subject microbiomes 
● 
Changes in baseline in biomarkers 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
3.3. Treatments 
 
OV101 is formulated as the monohydrate form (4,5,6,7-tetrahydro-isoxazolo[5,4-c]-pyridin- 
3-ol, monohydrate) in a white size 2 capsule. The capsule contains 5.645 mg of OV101 
monohydrate, which corresponds to 5.0 mg of OV101 (Table 1). 
 
Table 1 Pharmaceutical Composition of OV101 for the 5-mg Capsule 
 
Component 
Function 
Amount (mg) 
OV101a 
Active compound 
5.645 
Microcrystalline cellulose 
Diluent 
138.6 
Magnesium stearate 
Lubricant 
0.725 
Size 2 hard-gelatin capsule 
- 
60 
a Delivered as the zwitterion monohydrate. One gram of the anhydrous free zwitterion is equivalent to 1.129 g of the zwitterion 
monohydrate. 
 
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. 
 
Subjects will take all doses orally (assisted by an LAR/caregiver, if necessary) TID (morning, 
afternoon, evening), at approximately the same times each day, for the duration of the 12-week 
treatment period. The morning and afternoon doses should be taken with light low-fat food (a 
glass of low-fat milk would qualify as food), and the afternoon dose should be taken at least 6 
hours after the morning dose. The evening dose should be taken 30 minutes before bedtime. 
Capsules may be opened and the contents sprinkled onto 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 specifically how each capsule was taken (e.g., swallowed 
whole or taken in 1 teaspoon of semiliquid food). 
 
3.4. Dose Adjustment/Modification 
 
There will not be any dose adjustments permitted during the study. 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
4. GENERAL STATISTICAL CONSIDERATIONS 
 
All statistical analyses will be performed using SAS® Version 9.3 or higher. 
 
All clinical study data will be presented in subject data listings. In by-treatment group 
descriptive presentations, the 3 randomized treatment groups will be presented separately as 
well as overall. 
 
Descriptive statistics (number of subjects, mean, standard deviation (SD), median, Q1, Q3, 
minimum, and maximum) will be presented by treatment group for continuous variables and 
their changes from baseline. In addition, 95% CIs for the mean change from baseline will be 
provided for continuous variables. Graphical displays will be utilized to investigate trends over 
time and dose and the relationship between certain variables and differences between age 
groups. Ordinal variables with sufficient numerical categories (e.g., 7-point scales of PGI-S 
and CGI-S) and subscale total scores from questionnaires will be treated as continuous 
variables. 
 
Categorical (not treated as continuous) endpoints (including AE incidence and binary 
endpoints) will be summarized by frequency and percentage. Frequencies and percentages will 
be presented for the shifts in these categories (e.g., low to normal, low to high, high to low) 
from baseline to each post-baseline assessment time point for scales with categorical variables. 
If there are missing values, the number missing will be presented (as a category), but without 
a percentage. 
 
For all analyses, ‘Baseline’ refers as the last non-missing observation on or before the date of 
first dose of study medication. Change from baseline will be calculated by subtracting baseline 
value from post-baseline assessment for each subject. 
 
If there are multiple records within a pre-specified visit window the non-missing visit closest 
to the scheduled visit day will be included in the summary tables. 
 
The following reporting conventions apply generally to tables, listings and figures: 
● All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value. Minimum and maximum will be formatted to the same 
decimal as the measured value; 
● All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses. In the case the numerator is equal to the denominator, the percentage 
should be presented as (100) instead of (100.0). For TEAEs, the number, percentage, 
and event incidence will be presented in the form of xx (xx.x) [E], where E is the 
number of events; 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
●  All listings will be sorted for presentation in order of randomized treatment group, 
study center, subject, and date of procedure or event; 
● All analysis and summary tables will have the analysis population sample size for each 
treatment group in the column heading (i.e., number of subjects); 
● P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as “<0.0001” and p-values that round to 1.0000 will be presented as 
“>0.9999”; 
● The day of first dose of study drug, OV101, will be defined as Day 1. For day 
calculation, if date is before first dose date then day=date - first dose date, if date is 
after first dose date then day=date - first dose date + 1; 
● Listings of all data will identify the age group (adolescent/adult) of each subject. 
 
4.1. Visits and Day Ranges 
 
Since it is not always possible for all study participants to come in for their clinic visits on the 
exact day specified in the protocol schedule, the ‘Week’ of a subject visit will be defined by 
the following relative day ranges. 
 
Visit 
Target 
Study Days 
Baseline 
Day 1 
Day 1 
Phone 1 
Day 8 
Days 2 to 10 
Week 2 
Day 15 
Days 11 to 25 
Phone 4 
Day 29 
Days 26 to 32 
Week 6 
Day 43 
Days 33 to 53 
Phone 8 
Day 57 
Days 54 to 64 
Phone 10 
Day 71 
Days 65 to 74 
Week 12 (EOT) 
Day 85 
Days 75 to 93 
Week 16 (EOS) 
Day 113 
Days 94 to 127 
 
4.2. Sample Size 
 
A sufficient number of subjects (36 estimated) will be enrolled to ensure that 30 evaluable 
subjects complete 12 weeks of treatment. Subjects will be randomly assigned to the 3 OV101 
total daily dosing regimens in a 1:1:1 ratio, stratified by age group (adolescents/adults), with a 
target ratio of 1:1 between adolescents and adults. 
 
The main emphasis in reporting the data will be on descriptive statistics and estimation with 
95% confidence intervals (CIs). 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
For the objective of estimating the overall subject incidence of TEAEs (for the 3 OV101 total 
daily dose arms combined), the precision varies with true incidence, e.g., a true incidence of 
20% would be estimated with a 13.9% precision (half-width of the 2-sided 95% CI, assuming 
N = 30). Table 2 contains the estimated precision for different incidence rates, using the Wilson 
method of calculating a confidence interval for a binomial proportion. 
 
Table 2 Incidence Rates and Corresponding Precision 
 
True TEAE 
Incidence Rate 
10% 
13.3% 
20% 
23% 
30% 
Expected n with 
a TEAE (N=30) 
3 
4 
6 
7 
9 
Expected 
proportion, p 
0.100 
0.133 
0.200 
0.233 
0.300 
95% CI 
(3.5%,25.6%) 
(5.3%,29.7%) 
(9.5%,37.3%) 
(11.8%,40.9%) 
(16.7%,47.9%) 
Precision (half- 
width of CI) 
11.1% 
12.2% 
13.9% 
14.6% 
15.6% 
Note: All CIs are 2-sided and 95% CIs are calculated using Wilson’s method. 
Abbreviations: n, number of subjects observed; N, total number of evaluable subjects in the study (all treatment 
groups); TEAE, treatment-emergent adverse event. 
 
4.3. Stratification, Randomization, and Blinding 
 
An interactive web response system (IWRS) will be used to administer the randomization 
schedule. The study will be performed in a double-blind manner, with the subjects, 
LAR/caregivers, investigators, study personnel, monitors, and study sponsor blinded to the 
identity of all study drug. 
 
Subjects who meet all eligibility criteria will be randomly assigned at Baseline to the 5 mg/day, 
10 mg/day, or 15 mg/day OV101 treatment group in a 1:1:1 allocation ratio. It is anticipated 
that approximately 36 male subjects will be enrolled (to obtain 30 evaluable subjects), while 
maintaining a 1:1 target ratio between adolescents (13 to17 years old, inclusive) and adults (18 
to 22 years old, inclusive). The randomization schedule will be stratified by age (13 to 17, 
inclusive; 18 to 22, inclusive). It will also use an appropriate block size, which will not be 
revealed. 
 
4.4. Analysis Set 
 
Randomized Analysis Set: The randomized analysis set will consist of all randomly assigned 
subjects. This will be used for summaries of subject disposition, demographics, and other 
baseline characteristics. 
 
Full-Analysis Set (FAS): The FAS will consist of all randomly assigned subjects who receive 
at least 1 dose of study drug and have at least 1 postbaseline efficacy assessment. Following 


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the intent-to-treat principle, subjects will be analyzed according to the treatment they are 
assigned to at randomization, regardless of compliance or any deviations from the study 
protocol. All efficacy evaluations will be carried out on the FAS. 
 
Safety Set: The safety set will consist of all subjects who receive at least 1 dose of study drug. 
All analyses using the safety set will group subjects according to treatment actually received. 
All safety evaluations will be carried out on the safety set. 


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5. SUBJECT DISPOSITIONS 
 
5.1. Dispositions 
 
The number and percentage of subjects included in the analysis sets (safety, randomized, and 
full analysis sets) will be presented overall and by treatment group. Tables will indicate number 
of subjects who completed the study, number and percentage of subjects who completed the 
treatment, and the number of subjects who discontinued study and treatment for any of the 
following reasons: 
 
 Does not meet I/E criteria 
 Adverse Event 
 Lab Results Clinically Significant 
 Symptoms not consistent with protocol 
 Lost to Follow-up 
 Physician Decision 
 Withdrawal by Subject/Withdraw Assent 
 Death 
 Other 
 
These tables will be summarized by treatment group and overall. Disposition data will be 
summarized and provided in subject listings. The other reasons will be specified in the subject 
listings. 
 
5.2. Protocol Deviations 
 
A deviation from the protocol is an unintended or unanticipated departure from the procedures 
or processes approved by the sponsor and the Institutional Review Board (IRB)/ Independent 
Ethics Committee (IEC) and agreed to by the investigator. A significant deviation occurs when 
there is non-adherence to the protocol by the subject or investigator that results in a significant, 
additional risk to the subject. Significant deviations can include non-adherence to inclusion or 
exclusion criteria, enrolment of the subject without prior sponsor approval, or non-adherence 
to Food and Drug Administration (FDA) regulations or International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) guideline. Relevant significant protocol 
deviations, with impacts to key safety and efficacy endpoints, will be summarized in a table 
by treatment group and overall. All protocol deviations will be displayed in a listing with 
significant and relevant deviations indicated. 


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6. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
 
6.1. Demographic 
Demographic characteristics include age, race, ethnicity, and enrollment by study center. 
Summary statistics by treatment group and overall will include counts and percentages for 
discrete variables, and number of subjects, mean, SD, median, minimum and maximum for 
continuous variables. 
The following variables will be summarized by treatment group: 
 
1) Continuous variable: age (years) 
2) Categorical/discrete baseline and demographic variables: age [adolescent (13 to 17, 
inclusive), adult (18 to 22, inclusive)], ethnicity (Hispanic or Latino, Not Hispanic or 
Latino), race (American Indian or Alaska Native, Asian, Black or African-American, 
Native Hawaiian or Other Pacific Islander, White or Caucasian, or Other), enrollment 
by study center 
 
6.2. Baseline Characteristics 
 
Baseline characteristics include baseline body weight (kg), height (cm), alcohol use, 
Intelligence Quotient (IQ) by Stanford-Binet-5, Diagnostic and Statistical Manuel of Mental 
Disorders (DSM-5) autism spectrum disorder criteria and Molecular FXS test. 
 
Summary statistics by treatment group and overall will include counts and percentages for 
discrete variables, and mean, SD, median, minimum and maximum for continuous variables. 
 
6.3. Medical History 
 
6.3.1 General Medical History 
 
General medical history will be coded by MedDRA Version 20.1 or higher and summarized 
by SOC and PT for each treatment group as well as overall. Subject medical history including 
specific details will be presented in a listing. Body system will be presented in descending 
order for all subjects (descending order by counts in the Total column). 
 
6.4. Inclusion and Exclusion Criteria 
 
All inclusion/exclusion information on screen fail subjects will be included in a by-subject 
listing. The listing will include whether all criteria were satisfied. For subjects who did not 
satisfy the criteria, the criterion number will be listed with the deviation, along with whether 
an exception was obtained. 


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7. TREATMENTS AND MEDICATIONS 
 
7.1. Prior and Concomitant Medications and Procedures 
 
Therapies, procedures, and medications started and stopped prior to the start of study treatment 
are referred to as prior therapies and prior medications, respectively. Therapies, procedures, 
and medications that started prior to treatment and continued on treatment as well as those that 
started during treatment are referred to as concomitant therapies and concomitant medications. 
In order to define whether a medication with missing start or stop dates is a concomitant 
medication, refer to the following additional criteria. 
 
● if both the start and stop dates of a particular medication are missing, that medication 
will be considered concomitant; 
● if the start date of a medication is missing and the stop date of that medication falls on 
or after the dose date, that medication will be considered concomitant; 
● if the start date of a medication is missing and the stop date of the medication is prior 
to the dose date, that medication is considered not concomitant; 
● if the start date of a medication is prior to the dose date and the stop date of the 
medication is missing, that medication is considered concomitant. 
 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD) version December 2017 or later and will be classified by Anatomical 
Therapeutic Class (ATC) level 4 and preferred term (PT). For the presentation of concomitant 
medications, the ATC level 4 terms will be sorted alphabetically, and within ATC level 4 term, 
the PT will be used and presented by decreasing total frequency overall. 
 
The number and percentage of subjects who took at least 1 medication during the double-blind 
period as well as the number and percentage of subjects who took each type of medication will 
be presented for each treatment group and overall. 
 
Prior and concomitant medications and procedures will be presented in separate listings. 
 
7.2. Study Treatments 
 
7.2.1 Extent of Exposure 
 
Total capsules taken will be derived as the total number of capsules dispensed minus the total 
number of capsules returned and the duration of exposure will be computed as the last dose 
date – first dose date +1 and will be presented in categories by age group. The duration of 
exposure will be categorized as follows: fewer than 1 day, 1 to < 8 days, 8 to < 15 days, 15 to 
< 43 days, 43 to < 85 days, and 85 days or more. 
 
Subject listing of study treatment exposure will be provided. 


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7.2.2 Treatment Compliance 
 
Treatment compliance of OV101 capsules will be summarized by treatment group over the 
entire treatment period. Compliance of placebo capsules will not be determined. Treatment 
compliance will be summarized by treatment group and overall. 
 
Compliance (%) = (Actual number of OV101 capsules/ Expected number of OV101 capsules) 
*100%. 
 
The actual number of active OV101 capsules taken will be derived as the sum of: 1) 
number of capsules dispensed at Baseline minus number of capsules returned at Week 
6, and 2) number of capsules dispensed at Week 6 minus number of capsules returned 
at EOT. 
 
The expected number of OV101 capsules will be derived by multiplying the daily dose 
(1, 2, or 3 active OV101 capsules for the 5, 10, or 15 mg groups, respectively) by 
duration of exposure (see Section 7.2.1). 
 
The number of capsules dispensed and the number remaining will be tracked and 
recorded by individual bottle (labeled “Morning,” “Afternoon,” or “Evening”). 
 
A subject is compliant if overall compliance is >=80%. 
 
Dosing error specification (missed dose, capsule not taken in usual manner, extra capsules 
taken, wrong dose taken and others), time of dosing error (morning, afternoon, evening), and 
reasons for missed dose (e.g., forgot, subject refused, subject had side effects so parent decided 
to give a drug holiday and other reasons) for all dispensed capsules, both active or placebo, 
will be listed. 


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8. EFFICACY ANALYSES 
 
The primary endpoint of the study is a safety endpoint and not an efficacy endpoint. 
 
8.1. 
Secondary Efficacy Analysis 
 
Descriptive statistics will be presented for continuous variables and their changes from 
baseline. 
 
Exploratory modelling will be conducted on the efficacy variables using an MMRM to further 
investigate any trends evident in the descriptive statistics and to inform a future study. In case 
of exploratory modelling, the MMRM analysis will be performed on the change from baseline 
or the post-baseline result (depending on the endpoint) with age and baseline (if appropriate) 
as covariates, daily dosing regimen, visit, and age group as fixed effects, and visit by daily 
dosing regimen interaction. An unstructured covariance structure will be assumed. From this 
model, the least squares mean change from baseline and the corresponding 95% CI will be 
presented for each daily dosing regimen and the total (all regimens) at each post-baseline visit. 
The least squares mean difference and the corresponding 95% CI will be presented for each 
pairwise comparison between the 3 daily dosing regimens at each week. The least squares 
mean changes from baseline and corresponding 95% CIs will be plotted at each time point by 
daily dosing regimens. 
 
In the case of a statistically significant age group main effect (P<0.1) in the MMRM or age 
effects deemed evident in descriptive statistics, the mean changes with 95% CI described above 
will be estimated for each age group separately as well as overall; this will be achieved by 
inclusion of an additional term (age by week by daily dosing regimen interaction) in the 
MMRM. In this case, these additional estimates and 95% CI will be tabulated and plotted. 
 
8.1.1 Aberrant Behavior Checklist-Community (ABC-C) 
 
The Aberrant Behavior Checklist-Community (ABC-C) is a 58-item questionnaire completed 
by the LAR/caregiver that assesses a wide range of behaviors, including irritability, 
lethargy/social withdrawal, inappropriate speech, hyperactivity, stereotypic behavior, and 
social avoidance. Each item is rated on a scale of 0 to 3 (“not at all a problem” to “the problem 
is severe in degree”). The ABC-C will be scored 2 ways: according to the original method used 
to assess a population with a variety of disabilities (Aman et al 1985) and according to a method 
adapted for FXS that has a 6-factor structure (Sansone et al 2012). 


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The original method includes 5 subscales with the sub scores derivation: 
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 
 
The method adapted for FXS subscales will be derived as follows: 
SUBSCALES 
Sum of Questions 
Irritability 
2, 4, 7, 8, 10, 14, 18, 19, 21, 24, 29, 34, 36, 41, 47, 50, 52, 57 
Hyperactivity 
1, 13, 15, 31, 38, 39, 44, 48, 54 
Lethargy/Social Withdrawal 
12, 20, 23, 25, 28, 32, 37, 40, 43, 51, 53, 55, 56, 58 
Social Avoidance 
5, 16, 30, 42 
Stereotypic Behavior 
6, 11, 17, 35, 45, 49 
Inappropriate speech 
9, 22, 33, 46 
 
The mean change of ABC-C total and subscale scores according to the original method and 
according to the method adapted for FXS, at Week 2, Week 6, and Week 12 from baseline will 
be analyzed as described in Section 8.1. 
 
For ABC-C, the maximum amount of missing data that can be tolerated varies by subscale in 
original method. The following upper limits of missing items tolerated for each subscale are: 
(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 (unscored) by the rater, then the associated subscale 
score is not computed at all; instead, list the data as missing for those subscales. 
 
When the amount of missing data is tolerated, 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. For example, 
values of 13 items out of 15 Irritability questions are applicable with a sum of 23, then the prorated 
score of Irritability is (15/13)*23=26.54. 
 
For subscales in FXS method, if the traditional subscales can be derived then the corresponding 
FXS subscale scores will be calculated. For FXS Social Avoidance subscale (4-item scale), if 
more than 1 item is missing then the subscale will be missing. Assuming values of 14 items 
out of 18 FXS-Irritability questions are applicable with a sum of 25, as the original Irritability 
is calculated, the FXS-Irritability score is prorated as (18/14)*25=32.14. 


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Subjects with total score of 16 or lower at the Baseline visit will be excluded from analysis of 
ABC-C, while sensitivity analysis with all subjects involved will be conducted. 
 
The ABC-C total score will be calculated only when all associated subscales scores are derived 
and not missing. 
 
8.1.2 Anxiety, Depression, and Mood Scales (ADAMS) 
 
The Anxiety, Depression, and Mood Scales (ADAMS) is a caregiver-completed report that 
screens comprehensively for anxiety and depression in persons with intellectual disability and 
consists of 28 items grouped into 5 subscales that assess the frequency and severity of 
manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, and 
obsessive/compulsive behavior (Esbensen et al 2003). 
 
Sub scores will be obtained as follows: 
SUBSCALES 
Sum of Questions 
Manic/Hyperactive behavior 
3, 4, 12, 17, 22 
Depressed mood 
5, 9, 10, 14, 18, 23, 28 
Social avoidance 
2, 6, 13, 19, 21, 25, 27 
General anxiety 
1, 3, 7, 11, 15, 24, 26 
Obsessive/compulsive behavior 
8, 16, 20 
 
Mean change from baseline to Week 2, Week 6, and Week 12 on the ADAMS score and 
subscale scores will be analyzed as described in Section 8.1. Missing data convention from the 
provider will be used for missing assessments and scores. Otherwise, missing data from the 
assessment will be kept as missing. 


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8.1.3 Repetitive Behavior Scale-Revised (RBS-R) 
 
The Repetitive Behavior Scale-Revised (RBS-R) is a caregiver-completed, 43-item 
questionnaire assessing a variety of repetitive behaviors with 6 behavior subscales: 
stereotyped, ritualistic, self-injurious, compulsive, restricted, and sameness (Bodfish et al 
2000). 
 
Overall total RBS-R raw score will be obtained by getting the sum of items 1-43. The number 
of items endorsed (defined as the number of items rated 1, 2, or 3) and overall will be derived 
and summarized. Missing data convention from the provider will be used for missing 
assessments and scores. Otherwise, missing data from the assessment will be kept as missing. 
 
Subscale scores will be computed as follows: 
SUBSCALES 
Sum of Questions 
Stereotyped Behavior 
1-6 
Self-Injurious Behavior 
7-14 
Compulsive Behavior 
15-22 
Ritualistic Behavior 
23-28 
Sameness Behavior 
29-39 
Restricted Behavior 
40-43 
 
Change from baseline to Week 2, Week 6, and Week 12 on the RBS-R total and subscale raw 
scores and number of items endorsed will be analyzed as described in Section 8.1. 
 
8.1.4 Conner’s 3rd Edition 
 
The Conner’s 3rd Edition (Conner’s 3; North Tonawanda Multi-Health System, North 
Tonawanda, NY) is designed to assess attention deficit hyperactivity disorder, and it will be 
used to collect LAR/caregiver observations of subject behavior. The assessment of behavior in 
neurodevelopmental disorders, such as FXS, frequently relies upon proxy report. The long 
form of Conner’s 3 is needed to assess inconsistency (reporter reliability) and will be 
administered at Screening only. The short form of Conner’s 3 will be administered as an 
outcome assessment at the baseline, Week 2, Week 6, Week 12, and EOS visits. 
 
The Inconsistency Index/Response Style Analysis is a categorical variable obtained using two 
variables obtained at the Screening visit using the long form of Conner’s 3: Inconsistency Index 
Raw Score and Inconsistency Index Number of Differentials ≥ 2. If the Inconsistency Index 
Raw Score ≥ 7 and Inconsistency Index Number of Differentials ≥ 2, then there is a possible 
inconsistent response style. These data will be summarized and listed. 
 
The Raw sub scores for Content scales will be provided in the eCRF. Content scales include 
inattention, hyperactivity/impulsivity, learning problems, executive functioning, 
defiance/aggression, peer relations. The mean change of content subscale scores at Week 2, 


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Week 6, and Week 12 from baseline will be analyzed as described in Section 8.1. Subjects 
with inconsistent response style at Screening visit were excluded. Missing data convention 
from the provider will be used for missing assessments and scores. Otherwise, missing data 
from the assessment will be kept as missing. 
 
8.1.5 Short Sensory Profile-2 
 
The Short Sensory Profile-2 is a caregiver questionnaire to evaluate a subject’s sensory 
processing patterns in the context of home, school, and community-based activities. 
 
Sensory Processing Raw Total score is the sum of items 1-14 and Behavioral Responses Raw 
Total score is the sum of items 15-34. Raw scores of the subscales will be derived as follows 
and will be analyzed as described in Section 8.1: 
SUBSCALES 
Sum of Questions 
Seeking 
6-8, 11, 14, 31, 32 
Avoiding 
16-20, 22-24, 26 
Sensitivity 
1-5, 21, 25, 28, 29, 33 
Registration 
9, 10, 12, 13, 15, 27, 30, 34 
 
Change from baseline in Sensory Processing Raw Total score, Behavioral Responses Raw 
Total score and subscale scores at Week 2, Week 6, and Week 12 will be analyzed as described 
in Section 8.1. Missing data convention from the provider will be used for missing assessments 
and scores. Otherwise, missing data from the assessment will be kept as missing. 
 
8.1.6 Clinical Global Impressions Scales 
 
The CGI-S scale will be used by the investigator to assess the severity of symptoms, and the 
CGI-I scale will be used by investigators to assess improvement from baseline. The CGI-S has 
been adapted to capture specific characteristics commonly present in the FXS population. Both 
CGI-S and CGI-I will be conducted by a clinician with experience in FXS. 
 
A dichotomous responder variable will be defined whether or not there is improvement in any 
CGI-I. Response is defined as improvement in any of the CGI-I survey questions, with 
improvement indicated by a response of “Very much improved”, “Much improved”, and 
“Minimally improved” compared to time of enrollment. The CGI-I responder endpoint will be 
compared between treatments (OV101 5mg vs. OV101 10mg; OV101 5mg vs. OV101 15mg; 
OV101 10mg vs. OV101 15mg) at week 12 and exact test will be used to test for the difference 
of the treatments. 
 
CGI severity (CGI-S) and CGI improvement (CGI-I) scores as well as by-domain CGI-S sub 
scores will be provided in the eCRF Domains includes: Anxiety, ADHD, 
Communication/Connectedness, Repetitive and Restrictive Behavior, Disruptive Behavior, 
and Activities of Daily Living. 


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The mean change of CGI-S score and by-domain CGI-S sub scores at Week 2, Week 6, and 
Week 12 from baseline will be analyzed as described in Section 8.1. 
 
The frequencies of CGI-I categories at Week 2, Week 6, and Week 12 will be summarized. 
 
Responder analysis will be performed to test difference in CGI-I between treatments with 
exact test at Week 12 using observed data. Additionally, a sensitivity analysis will be 
conducted at Week 12 using last observation carried forward (LOCF) method for missing 
data. 
 
8.2. 
Exploratory Efficacy Analysis 
 
8.2.1 Caregiver-Completed Endpoints 
 
8.2.1.1 Behavior Assessment System for Children, 3rd Edition (BASC-3 PRQ) 
 
The Behavior Assessment System for Children, 3rd Edition, Parenting Relationship 
Questionnaire (BASC-3 PRQ) provides information on the relationship between a caregiver 
and a child across multiple dimensions (Pearson, New York, NY). It yields the following 
subscale scores: attachment, communication, discipline practices, involvement, parent 
confidence, satisfaction with school, and relation frustration. The questionnaire is written at a 
third grade level and also calculates a number of response validity scores, such as consistency 
and response pattern, to detect careless or exaggerated responding. It includes normative 
samples for both female and male raters that are closely matched to the US Census population 
estimates. 
 
Content Domains raw scores (Attachment, Communication, Discipline, Involvement, 
Parenting Confidence, Satisfaction with School, and Relationship Frustration) at Week 6 and 
Week 12 will be summarized. Missing data convention from the provider will be used for 
missing assessments and scores. Otherwise, missing data from the assessment will be kept as 
missing. 
 
Validity Index Summary Raw Scores and Category Assignment (F Index, D Index, Response 
Pattern Index, and Consistency Index) will be summarized. 
 
8.2.1.2 Parent Global Impressions Scales 
 
The Parent Global Impressions-Severity (PGI-S) scale will be completed by the LAR/caregiver 
to assess the severity of symptoms, and the Parent Global Impressions-Improvement (PGI-I) 
scale will be used by the LAR/caregiver to assess improvement from baseline. The PGI-S has 
been adapted to capture specific characteristics commonly present in the FXS population. 


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Severity of Participant’s condition will be collected in the eCRF and the change from baseline 
at Week 2, Week 6, and Week 12 will be analyzed as described in Section 8.1. 
 
Improvement of Participant’s condition will be collected in the eCRF and the frequencies at 
Week 2, Week 6, and Week 12 will be summarized. Missing data convention from the provider 
will be used for missing assessments and scores. Otherwise, missing data from the assessment 
will be kept as missing. 
 
8.2.1.3 Pediatric Quality of Life Inventory 
 
The Pediatric Quality of Life Inventory (PedsQL) generic core scales and Multidimensional 
Fatigue Scale will be administered in this study (Varni et al 2004). The generic core scales 
include 23 items covering the domains of physical, emotional, social, and school functioning. 
The Multidimensional Fatigue Scale contains 18 items measuring general fatigue, sleep/rest 
fatigue, and cognitive fatigue. 
 
PedsQL Generic Core and Multidimensional Fatigue transformed scores, mean scores for the 
domains, and total scores will be derived. Each item will be reverse scored and linearly 
transformed to a 0-100 scale, so that higher scores indicate better Health-Related Quality of 
Life. Items will be transformed as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. 
 
Transformed scores will be used to calculate the 3 mean domain scores, and total score on the 
multidimensional fatigue scale as follows: 
 
DOMAIN 
Mean Score* 
General Fatigue 
Mean of 6 transformed items under ‘General Fatigue’ 
Sleep/Rest Fatigue 
Mean of 6 transformed items under ‘Sleep/rest Fatigue’ 
Cognitive Fatigue 
Mean of 6 transformed items under ‘Cognitive Fatigue’ 
Total 
Mean of all transformed items 
* If more than 50% of the items in the scale are missing, the mean domain score should not be computed. If more than 50% 
of the items are completed, mean of the completed items in a domain scale will be imputed. 
 
Transformed scores will be used to calculate the 4 mean domain scores, total score, and 
Psychosocial Health Summary Score on the generic core scale as follows: 
 
DOMAIN 
Mean Score* 
Physical Functioning 
Mean of 8 transformed items under ‘Physical Functioning’ 
Emotional Functioning 
Mean of 5 transformed items under ‘Emotional Functioning’ 
Social Functioning 
Mean of 5 transformed items under ‘Social Functioning’ 
School Functioning (for Teens 
ages, 13-18) or Work/Studies 
Functioning (for Young Adults, 
ages 18-22) 
Mean of 5 transformed items under ‘School Functioning” or 
‘Work/Studies Functioning’ 


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Psychosocial Health Summary 
Score 
Mean of transformed items under ‘Emotional Functioning’, 
‘Social Functioning’, and “School Functioning” or 
‘Work/Studies Functioning’ mean scores 
Total 
Mean of all transformed items 
* If more than 50% of the items in the scale are missing, the mean domain score should not be computed. If more than 50% 
of the items are completed, mean of the completed items in a domain scale will be imputed. 
 
Change from baseline in the mean total score and mean scores of the domains for both PedsQL 
generic core and multidimensional will be analyzed at week 6 and EOT. 
 
8.2.1.4 Children’s Sleep Habits Questionnaire 
 
The Children’s Sleep Habits Questionnaire (CSHQ) is a caregiver-completed assessment of 
sleep behaviors in children and adolescents (Owens et al 2000). The abbreviated version of 
this questionnaire includes 33 items that assess sleep habits and possible difficulties with sleep. 
The LAR/caregiver will be asked to recall the subject’s sleep behaviors over the preceding 
week. 
 
The CHSQ consists of 8 domains with their sub scores and will be derived as follows: 
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 
R- reversed scored. 
 
Analysis as described in Section 8.1 will be used to analyze the change from baseline in CHSQ 
domains at Week 2, Week 6, and Week 12. 
 
Subscale scores of CSHQ are not calculated if >= 50% of the subscale answers are missing. 
When < 50% of subscale answers are missing, the subscale score will be prorated following 
the steps described in Section 8.1.1. For example, 4 out of 6 Bedtime Resistance questions are 
answered with a sum of 9, then the prorated score of Bedtime Resistance is (6/4)*9=13.5. 
 
CSHQ total will be calculated if all subscales are not missing. 
 
8.2.1.5 Sleep Diary 
 
A paper sleep diary will be completed by each subject’s LAR/caregiver, on behalf of the 
subject. Endpoints assessed by the sleep include how long it took the subject to fall asleep 


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Missing data convention from the provider will be used for missing assessments and scores. 
Otherwise, missing data from the assessment will be kept as missing. 
 
 
(sleep onset latency [SOL]), the amount of time the subject was awake during the night 
(WASO), the total amount of sleep obtained (total sleep time [TST]), daytime sleepiness, 
defined as duration of napping in the daytime, and number of times subject woke up at night. 
The sleep diary will be completed each day during the 7 days immediately preceding each 
clinic visit after screening. 
 
Sleep Parameters 
Derivation 
Sleep Onset Latency (SOL) 
in minutes 
[(First night: time to sleep – time subject went to bed) + 
(Second night: time to sleep – time subject went to bed) + 
(Third night: time to sleep – time subject went to bed) + 
(Fourth night: time to sleep – time subject went to bed) + 
(Fifth night: time to sleep – time subject went to bed) + (Sixth 
night: time to sleep – time subject went to bed) + (Seventh 
night: time to sleep – time subject went to bed)]/7 (or number 
of days with non-missing values) 
Note: For sleep time, consider the time closest on or after the 
time the subject went to bed on the same day 
WASO (minutes) 
Sum (time to sleep – time to wake from the previous log), 
considering all records between the time subject went to bed 
until subject woke up, then take the weekly average using the 
number of days with non-missing values. 
TST (hours) 
The weekly average, using the number of days with non- 
missing values, of total sleep time, converting the unit into 
hours. 
Daytime Sleepiness (minutes) 
The weekly average, using the number of days with non- 
missing values, of (time to sleep – time to wake), considering 
only records on the same day before subject went to bed 
Number of times subject 
woke in the nights (counts) 
The weekly average, using the number of days with non- 
missing values, of number of records from WASO 
considering all records between the time subject went to bed 
until subject woke up. 
 
Weekly average of sleep parameters will be calculated with missing data excluded. 
 
The baseline values of actigraphy parameters will be obtained from data collected within 7 
days immediately preceding Day 1. 
 
 
Change from baseline on the sleep parameters at Week 2, Week 6, and Week 12 will be 
analyzed as described in Section 8.1. 


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Missing data convention from the provider will be used for missing assessments and scores. 
Otherwise, missing data from the assessment will be kept as missing. 
 
 
 
8.2.2 Clinician-Completed Endpoints 
 
8.2.2.1 Caregiver Top 3 Concerns Visual Analog Scale 
 
In Part 1 of the visual analog scale (VAS), LARs/caregivers will generate their top 3 FXS- 
associated concerns for the subject and rate these 3 concerns using a 10-cm visual analog scale, 
with troublesome behaviors anchored at one end with the descriptor “worst ever” and at the other 
end with the descriptor “no problem at all”. The investigator will then map each LAR/caregiver- 
generated concern onto one of the predefined FXS domains (i.e. Anxiety, ADHD, 
Repetitive/Stereotypic Behavior, Disruptive Behavior, Communication, Activities of Daily Living, 
or Socialization and Other) to which each behavior or symptom applies. The top 3 FXS-associated 
concerns selected at Baseline will be fixed and assessed at Week 2, Week 6 and Week 12. 
Part 2 of VAS will be used to rate three FXS-specific domains: Speech and Communication, 
Socialization, and Cognition. 
 
At a single visit, it is possible that one subject could have more than one concerns within one 
domain as these are based on parent report. In this case, the averaged value within one FXS-specific 
domain per subject will be applied in analysis. 
 
Change from baseline in 1) value of the top 3 FXS-associated concerns, in 2) value of FXS 
domains after mapping of concerns, and in 3) FXS-specific domains (Speech and 
Communication, Socialization, Cognition) for the subject will be summarized by Week 2, 
Week 6, Week 12, as described in Section 8.1. 
 
Missing data convention from the provider will be used for missing assessments and scores. 
Otherwise, missing data from the assessment will be kept as missing. 
 
8.2.2.2 Vineland Adaptive Behavior Scale 
 
The Vineland Adaptive Behavior Scale, 3rd Edition (VABS-3) caregiver interview form will 
be used to evaluate communication, socialization, and daily living skills of subjects to assess 
their overall adaptive functioning. This assessment is an interview of the caregiver by a trained 
qualified rater. 
 
Change from baseline in standard VABS domain scores (consisting of adaptive behavior 
composite, communication domain, daily living skills domain and socialization domain) and 
raw scores and v-scores for subdomains (Receptive, Expressive, Written, Personal Care, 
Domestic, Community, Interpersonal Relationships, Play and Leisure Skills, and Coping 
Skills) collected in the eCRF will be summarized and analyzed for Week 6 and Week 12, as 
described in Section 8.1. 


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Missing data convention from the provider will be used for missing assessments and scores. 
Otherwise, missing data from the assessment will be kept as missing. 
 
8.2.2.3 Pediatric Sleep Clinical Global Impressions Scales 
 
The Pediatric Sleep CGI scales were recently developed to measure pediatric insomnia in 
autism spectrum disorder and have been validated against the CSHQ and actigraphy (Malow 
et al 2016). Questions include the subject's ability to fall asleep and remain sleeping 
independently (i.e., apart from LAR/caregivers); bedtime resistance; sleep onset delay; night 
awakening; LAR/caregiver satisfaction with their child's current sleep patterns; family 
functioning, as affected by their child's current sleep patterns; and clinician's overall concern 
with the child's sleep. 
 
Pediatric Sleep CGI severity questions will be analyzed for Week 2, Week 6, and Week 12, as 
described in Section 8.1. 
 
Missing data convention from the provider will be used for missing assessments and scores. 
Otherwise, missing data from the assessment will be kept as missing. 
 
8.2.3 Direct Subject Assessment Endpoints 
 
8.2.3.1 Actigraphy 
 
Actigraphy is a noninvasive method of monitoring human rest/activity cycles. A small 
actigraph unit is worn to measure daytime and sleep activity. The actigraph unit stores motion 
data by clock time, and the data must be uploaded to an actigraphy database for analysis. The 
actigraphy data (including parameters such as: SOL, WASO, TST, NA, sleep efficiency, daily 
activity level, and sleep fragmentation) will be compared to the sleep diary data. The derivation 
of these parameters will be as follows: 
 
Sleep Parameters 
Derivation 
Sleep Onset Latency (SOL) 
Mean of Onset Latency (minutes), duration from 
the beginning of the rest period to the start of sleep 
onset, reported when interval type = sleep 
Total Sleep Time (TST) during 
night 
Take Sum of sleep time (minutes) where interval 
type = ‘sleep’ within each day then the Mean of this 
sum for an average score per day. Convert its unit to 
hours in analysis. 
Total Sleep Time (TST) during 
day 
Take Sum of sleep time (minutes) where interval 
type = ‘Active’ within each day then the Mean of 
this sum for an average score per day. Convert its unit to 
hours in analysis. 


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Wake After Sleep Onset 
(WASO) 
Mean of WASO when interval type = sleep 
Nocturnal Awakenings (NA) 
Mean of # Wake bouts when interval type = sleep 
Sleep Efficiency 
Mean of Efficiency (%) when interval type = sleep. 
Efficiency is defined as total sleep time as a 
fraction of the rest period (total time in bed). 
Daily Activity Level 
Take Sum of Total AC (counts) within each day 
then the Mean of this sum for an average score per 
day 
Sleep Fragmentation 
Sum of Fragmentation (%+%) when interval type = 
sleep 
 
The baseline values of actigraphy parameters will be obtained from data collected within 7 
days immediately preceding Day 1. 
 
The change from baseline in the subject actigraphy parameters will be analyzed for Week 2, 
Week 6, and Week 12, as described in Section 8.1. 
 
Missing data convention from the provider will be used for missing assessments and scores. 
Otherwise, missing data from the assessment will be kept as missing. 
 
8.2.3.2 Test of Attentional Performance for Children 
 
The KiTAP is an automated computer-based assessment of attentional performance developed 
and normed for a pediatric population. The KiTAP is suitable for assessment of function in 
individuals of various ages, including children, adolescents, and adults, with FXS (Knox et al 
2012). The task displays an “enchanted castle” animation and measures 8 aspects of attention: 
alertness, distractibility, flexibility, Go/NoGo, virtual scanning, vigilance, sustained attention, 
and divided attention. Only 4 of the 8 subtests will be administered in this study: alertness, 
distractibility, Go/NoGo, and flexibility. 
 
The change from baseline in the KiTAP (for the 4 sub-tests presented in the CRF: alertness, 
distractibility, flexibility, Go/NoGo) and their corresponding parameters (mean, stddev, 
correct, omissions, anticipations for alertness; mean, stddev, correct, errors for flexibility, and 
mean, stddev, correct, errors, omissions for Go/NoGo parameters; distractor mean, distractor 
correct, distractor errors, distractor omissions, no distractor mean, no distractor correct, no 
distractor errors, no distractor omissions, total mean, total correct, total errors, total omissions 
for distractibility parameter) will be analyzed for Week 6 and Week 12, as described in Section 
8. 1. 
 
If value of some of KiTAP parameter is missing from the Baseline visit, the value from the 
Screening visit can be used for analysis. Missing data convention from the provider will be 


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used for missing assessments and scores. Otherwise, missing data from the assessment will be 
kept as missing. 
 
8.2.3.3 Repeatable Battery for the Assessment of Neuropsychological Status 
 
The RBANS provides a brief individually administered battery to assess cognitive function in 
individuals 12 years of age and older (Randolph et al 1998). The full battery consists of 12 
subtests to assess immediate memory, visuospatial abilities, language, attention, and delayed 
memory. In this study, 6 subtests of the RBANS will be used: list learning (immediate 
memory), list recall (delayed memory), list recognition (delayed memory index), story memory 
(immediate memory index), story recall (delayed memory index), and picture naming 
(language index). Each subtest can be administered in 5 minutes or less. 
 
Subtests total scores will be derived in the eCRF and analysis as described in Section 8.1 will 
be used to analyze the change from baseline in the RBANS subset scores for Week 6 and Week 
12. 
 
If some subtest score of RBANS is missing from the Baseline visit, the subtest score from the 
Screening visit can be used for analysis. Missing data convention from the provider will be 
used for missing assessments and scores. Otherwise, missing data from the assessment will be 
kept as missing.  
 
8.2.3.4 Evoked Response Potential 
 
Electroencephalogram recordings will be used to characterize resting EEG and ERP and to  
assess treatment response and associated changes in cortical activity (Ethridge et al 2016).  
Subjects will passively listen to 150 pairs (S1, S2) of 5-msec broadband noise bursts (65 dB)  
separated by an inter-stimulus interval of 500 msec. Inter-trial intervals will be 4000 msec  
(average), for a total task duration of 11.25 minutes. Data from an electroencephalogram will  
be acquired continuously at a 1000 Hz sampling rate, and will be filtered online at 0.1 to 100  
Hz, amplified (12,500×), and digitized (1000 Hz). Participants will view a standard silent  
movie of their choice during electroencephalogram recording. If the participant in unable to  
cooperate for the ERP testing, he will not be withdrawn from the study. Some, but not all, sites  
will be capable of performing ERP testing. 
 
EEG parameters include 7 frequency bands: delta power, theta power, low alpha power, high  
alpha power, beta power, low gamma power, and high gamma power. Relative power of each  
frequency band is obtained by computing the proportion a band represents of the total power  
(i.e. sum of all 7 bands). Mean change from baseline in absolute and relative EEG parameters  
will be analyzed for Week 6 and Week 12, as described in Section 8.1.  
 
ERP parameters include N1-stim1-amplitude, N1-stim2-amplitude, N1-stim1-latency, N1- 
stim2-latency, P2-stim1-amplitude, P2-stim2-amplitude, P2-stim1-latency, and P2-stim2- 


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latency. The habituation of the response is calculated by N1-stim1 amplitude/N1-stim2  
amplitude. The mean change from baseline in ERP parameters will be analyzed for Week 6  
and Week 12 by site (and so site will be added as a fixed effect to the model), as described in  
Section 8.1. 
 
Missing data from the assessment will be kept as missing. 
 
8.2.4 Metabolomic Biomarkers 
 
The change from baseline in the metabolomic biomarkers will be summarized by treatment  
group and overall. 
 
Data generation and analysis will be conducted externally, and the results may be reported  
separately. 
 
8.2.5 Cheek Microbiome Assessments 
 
Data generation and analysis will be conducted by Gencove Inc (New York, NY), and the  
results may be reported separately.  
 
8.3. 
Pharmacokinetic Analysis 
 
Data generation and analysis will be conducted by Covance Bioanalytical Services, LLC and  
the results may be reported separately. 


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9. SAFETY ANALYSES 
 
All safety data analyses will be conducted by using the Safety Set. 
 
9.1. 
Adverse Events 
 
9.1.1 Incidence of Adverse Events 
 
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 randomization if any symptoms develop. 
 
A Treatment-Emergent Adverse Event (TEAE) is defined as any event AE not present before 
exposure to study drug or any event already present that worsens in either intensity or 
frequency after exposure to study drug and occurred within 30 days of last dose. TEAEs will 
be reported in tables regardless of seriousness. 
 
For listings, any events after pre-specified range above will be flagged in the outputs. 
 
The subject-incidence and event-incidence of TEAEs, TEAEs leading to study discontinuation, 
treatment-related TEAEs, serious TEAEs, severity of TEAEs, TEAEs with outcome of death, 
and seizure TEAEs will be summarized by treatment and overall. For summaries of severe or 
treatment-related AEs, for a given subject, the highest severity or relationship for a specific PT 
will be considered. Adverse events with missing start dates will be considered treatment 
emergent. All AEs will be coded using the most current Medical Dictionary for Drug 
Regulatory Affairs (MedDRA, version 20.1 or higher) and will be summarized by System 
Organ Class (SOC) and Preferred Term (PT). For each SOC and PT, a subject will be counted 
only once for subject-incidence tabulations. In addition, TEAE will be summarized by System 
Organ Class (SOC), High Level Group Term (HLGT), High Level Term (HLT), and Preferred 
Term (PT). For each SOC, HLGT, HLT, and PT, a subject will be counted only once for 
subject-incidence tabulations. The Wilson 95% CIs will be displayed for the proportion of 
subjects experiencing TEAEs as a total across the 3 dosing regimens. Additional overall AEs 
(including non-TEAEs) by PTs will also be provided. Detailed listings of AEs, SAEs, 
treatment-related AEs, and TEAEs leading to study discontinuation will be provided. 
 
9.1.2 Relationship of Adverse Events to Study Drug 
 
A TEAE is considered treatment-related if there is any causal relationship between the study 
medication. If the relationship of a TEAE is missing or the TEAE is possibly or probably 
related, the TEAE is reported as related. The number and percentage of subjects experiencing 
treatment-related TEAEs and number of events will be summarized. 


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9.1.3 Severity of TEAEs 
 
A summary of TEAEs by severity will be presented in a table. The severity that will be 
presented represents the most extreme severity captured on the eCRF page. The possible 
severities are ‘Mild,’ ‘Moderate,’ and ‘Severe’. In the TEAE severity table, if a subject reported 
multiple occurrences of the same TEAE, only the most severe TEAE is presented. TEAEs that 
are missing severity will be presented in tables as ‘Severe’ but will be presented in the data 
listing with a missing severity. 
 
9.1.4 Serious TEAEs 
 
A serious treatment-emergent adverse event is any untoward medical occurrence that, at any 
dose, results in death, life-threatening, requires hospitalization or prolongation of existing 
hospitalization, hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE, results in disability/incapacity, and congenital 
anomaly/birth defect. 
 
Serious TEAEs will be categorized and presented by SOC and PT in the same manner to that 
described in Section 9.1.1. 
 
9.1.5 TEAEs Leading to Study Discontinuation 
 
The number and percentage of subjects with TEAEs leading to study discontinuation and 
number of events will be categorized and presented by SOC and PT in the same manner to that 
described in Section 9.1.1. 
 
9.1.6 TEAEs with Outcome of Death 
 
The number and percentage of TEAEs with outcome of death and number of events will be 
tabulated by treatment and overall. Adverse events leading to death will be categorized and 
presented by SOC and PT in the same manner to that described in Section 9.1.1. 
 
9.1.7 Seizure TEAEs 
 
The number and percentage of subjects with seizure TEAEs and number of events will be 
categorized and presented by SOC and PT in the same manner to that described in Section 
9.1.1. 
 
9.2. 
Clinical Laboratory Evaluations 
 
All laboratory results are from PPD central laboratory and only standard results in SI unit will 
be summarized in the outputs. 


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Descriptive statistics for laboratory values at each time point and change from Baseline values 
to each post-baseline time points in clinical chemistry and hematology results will be 
summarized. 
 
Shift tables for laboratory parameters will be presented to show the change of normality from 
baseline to each post-baseline time point. For each continuous laboratory parameter, results 
will be classified as low, normal, or high relative to the parameter’s reference range. 
Listings of subjects with abnormal results will be provided. 
 
9.2.1 Hematology 
 
The parameters to be analyzed for hematology includes 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). 
 
9.2.2 Clinical Chemistry 
 
The parameters to be analyzed for clinical chemistry are 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, phosphate, potassium, alanine aminotransferase, aspartate 
aminotransferase, lactate dehydrogenase, sodium, chloride, bilirubin (total, direct), total 
protein, uric acid, and creatine phosphokinase. 
 
9.2.3 Urinalysis 
 
The parameters to be analyzed for urinalysis include macroscopic (pH, specific gravity, 
glucose, protein, ketones, nitrates, blood) and microscopic, reported only if present (red blood 
cells/high-power field, white blood cells/high-power field, casts, epithelial cells, crystals, 
granulation). These parameters will be summarized by treatment in shift tables comparing the 
results at each scheduled post-baseline visit with those at the baseline visit. 
 
9.3. 
Vital Signs 
 
Vital signs (temperature in °C, pulse rate [beats per minute], respiratory rate [breaths per 
minute], and systolic and diastolic blood pressure [mmHg]), weight (kg), and height (cm) will 
be summarized descriptively at Baseline and all post-baseline study time points by treatment 
group and overall. Change from baseline and post-baseline study time points will be 
summarized descriptively by treatment group and overall. 
Data listings will be provided. 


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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) at 
baseline and all post-baseline study time points will be summarized by treatment group and 
overall. 
Shift table and data listings will be provided. 
 
9.5. 
Clinical Assessment of Suicidality 
 
The number and percentage of subjects on each of the following questions will be summarized 
in a table by treatment and overall. 
 
● Suicidal ideation: Has the subject wished he were dead or wished he could go to sleep 
and not wake up? 
● Suicidal behavior: Has the subject made a suicide attempt? Has the subject done 
anything to harm himself? 
● Self-injurious behavior: Has the subject engaged in non-suicidal self-injurious 
behavior? 


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10. INTERIM ANALYSIS 
 
No interim statistical analysis will be performed. Periodic interim blinded review of safety data 
will be performed as part of routine pharmacovigilance activities. 


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11. OTHER STATISTICAL ISSUES 
 
11.1. 
Significance Levels 
 
The primary objective of this study is safety and no power calculations for the efficacy analyses 
have been planned in the sample size justification. 
 
No adjustment will be made for multiple testing, all p-values will be treated as exploratory and 
should be interpreted with caution. 
 
All testing will be two-sided and conducted at 0.05 level of significance except for interactions, 
which will be tested at the 0.100 significance level. 
 
11.2. 
Handling of Missing Data 
 
If a baseline assessment is missing, then the last screening assessment close to the baseline will 
be used as the baseline assessment. 
 
The maximum amount of missing data that can be tolerated and derivation of prorating 
subscale scores have been specified in Section 8.1.1. 
 
Last observation carried forward (LOCF) method will be applied to impute responder (binary) 
endpoints, including CGI-I responder, in associated sensitivity analyses (see Section 8.1.6). 
 
For CSHQ, rule of handling missing data and the derivation of prorating domain sub scores 
have been specified in Section 8.2.1.4. 
 
In general, missing data convention from the provider will be used for missing assessments 
and scores. Otherwise, missing data from the assessment will be kept as missing (if it is not 
specified). 


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12. CHANGES COMPARED TO THE PROTOCOL 
 
In Section 7.8.5 of the Protocol, p-value of 0.05 was applied as the level of significance in 
testing the effect of age group in MMRM. However, a p-value of 0.10 for age related 
interaction term was used in the model selection in the SAP. 


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13. REFERENCES 
 
Aman MG, Singh NN, Stewart AW, et al. Psychometric characteristics of the Aberrant 
Behavior Checklist. Am J Ment Defic. 1985;89(5):492-502. 
 
Bodfish JW, Symons FJ, Parker DE, et al. Varieties of repetitive behavior in autism: 
comparisons to mental retardation. J Autism Dev Disord. 2000;30(3):237-43. 
 
Cogram P, Deacon RJ, During MJ, et al. Gaboxadol normalizes behavioral abnormalities in a 
mouse model of fragile X syndrome. Poster presented at: 18th International Fragile X and 
Related Neurodevelopmental Disorders Workshop; 2017 Oct 12-16; Saint-Alexis-des-Monts, 
Quebec. 
 
Crawford DC, Acuña JM, Sherman SL. FMR1 and the fragile X syndrome: human genome 
epidemiology review. Genet Med. 2001;3(5):359-71. 
 
Esbensen AJ, Rojahn J, Aman MG, et al. Reliability and validity of an assessment instrument 
for anxiety, depression, and mood among individuals with mental retardation. J Autism Dev 
Disord. 2003;33(6):617-29. 
 
Ethridge LE, White SP, Mosconi MW, et al. Reduced habituation of auditory evoked potentials 
indicate cortical hyper-excitability in fragile X syndrome. Transl Psychiatry. 2016;6:e787. 
 
Hagerman R, Hoem G, Hagerman P. Fragile X and autism: intertwined at the molecular level 
leading to targeted treatments. Mol Autism. 2010;1:12. 
 
Hall SS, Lightbody AA, Reiss AL. Compulsive, self-injurious, and autistic behavior in 
children and adolescents with fragile X syndrome. Am J Ment Retard. 2008;113(1):44-53. 
 
Harris SW, Hessl D, Goodlin-Jones B, et al. Autism profiles of males with fragile X 
syndrome. Am J Ment Retard. 2008;113(6):427-38. 
 
Knox A, Schneider A, Abucayan F, et al. Feasibility, reliability, and clinical validity of the 
Test of Attentional Performance for Children (KiTAP) in fragile X syndrome (FXS). J 
Neurodev Disord. 2012;4:2. 
 
Malow BA, Connolly HV, Weiss SK, et al. The Pediatric Sleep Clinical Global Impressions 
Scale–a new tool to measure pediatric insomnia in autism spectrum disorders. J Dev Behav 
Pediatr. 2016;37(5):370-6. 
 
Owens J, Spirito A, McGuinn M. The Children's Sleep Habits Questionnaire (CSHQ): 
psychometric properties of a survey instrument for school-aged children. Sleep. 2000;23(8):1- 
9. 


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Randolph C, Tierney MC, Mohr E, et al. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 
1998;20(3):310-9. 
 
Sansone SM, Widaman KF, Hall SS, et al. Psychometric study of the aberrant behavior 
checklist in fragile X syndrome and implications for targeted treatment. J Autism Dev Disord. 
2012;42(7):1377-92. 
 
Varni JW, Sherman SA, Burwinkle TM, et al. The PedsQL™ Family Impact Module: 
preliminary reliability and validity. Health Qual Life Outcomes. 2004;2:55. 


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14. APPENDICES 
 
14.1. 
Imputation Algorithm for Partial and Missing Dates 
 
Adverse Event, Concomitant Procedures and Concomitant Medications 
 
● Partial/Missing Start Date 
o Missing day - Impute the 1st of the month unless month is same as month of 
first dose of study drug then impute first dose date 
o Missing day and month – impute 1st January unless year is the same as first 
dose date then impute first dose date 
o Completely missing – impute first dose date unless the end date suggests it 
could have started prior to this in which case impute the 1st January of the same 
year as the end date. When imputing a start date ensure that the new imputed 
date is sensible i.e. is prior to the end date of the AE or med. 
● Partial/Missing End Date 
o Missing day - Impute the last day of the month unless month is same as month 
of last dose of study drug then impute last dose date 
o Missing day and month – impute 31st December unless year is the same as last 
dose date then impute last dose date 
o Completely Missing – need to look at whether the AE/medication is still 
ongoing before imputing a date and also when it started in relation to study 
drug. If the ongoing flag is checked then assume that AE is still present / 
medication is still being taken (i.e. do not impute a date). If the AE/medication 
has stopped and start date is prior to first dose date then impute the 1st dose 
date, if it started on or after first dose date then impute a date that is after the 
last dose date. 


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14.2. 
Schedule of Study Procedures 
 
Visit Name 
Screening 
Baseline 
Phone 
1 
Week 2 
Phone 4 
Week 6 
Phone 8 
Phone 10 
EOT 
EOS 
Visit Window (days) 
-a 
- 
±2 
±3 
±2 
±3 
±2 
±2 
±3 
+14 
Dayb 
-21 to 1 
1 
8 
15 
29 
43 
57 
71 
85 
113 
Week 
- 
0 
1 
2 
4 
6 
8 
10 
12 
16c 
Obtained informed consent and assesnt 
X 
 
 
 
 
 
 
 
 
 
Verify Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Obtain medical history 
X 
X 
 
 
 
 
 
 
 
 
Conduct clinical assessmentd for FXS 
X 
 
 
 
 
 
 
 
 
 
Stanford-Binet-5 
X 
 
 
 
 
 
 
 
 
 
Review for DSM-5 autism spectrum disorder 
criteria 
X 
 
 
 
 
 
 
 
 
 
Molecular FXS Teste 
X 
 
 
 
 
 
 
 
 
 
PK sampling 
 
X 
 
X 
 
X 
 
 
X 
 
Biomarker assessment (plasma, cheek swab; 
optional) 
 
 
 
 
 
 
 
 
 
 
 X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Clinical assessment of suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
X 
 
X 
 
 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
X 
X 
Clinical laboratory tests 
X 
Xf 
 
X 
 
X 
 
 
X 
 
Randomization assignment 
 
X 
 
 
 
 
 
 
 
 
Adverse event inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense medication diary 
 
X 
 
 
 
X 
 
 
 
 
Review/collect 
medication 
diary, 
assess 
compliance 
 
 
 
X 
 
X 
 
 
X 
 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
 
Dispense study drug 
 
X 
 
 
 
X 
 
 
 
 
Collect unused study drug 
 
 
 
 
 
X 
 
 
X 
 
Caregiver-Completed Measures 
 
 
 
 
 
 
 
 
 
 
Aberrant Behavior Checklist-Community 
 
X 
 
X 
 
X 
 
 
X 
X 
Anxiety, Depression, and Mood Scales 
 
X 
 
X 
 
X 
 
 
X 
X 
Repetitive Behavior Scale-Revised 
 
X 
 
X 
 
X 
 
 
X 
X 
Conner’s 3rd Edition 
X (LF) 
X (SF) 
 
X (SF) 
 
X (SF) 
 
 
X (SF) 
X (SF) 
Short Sensory Profile-2 
 
X 
 
X 
 
X 
 
 
X 
X 
Children’s Sleep Habits Questionnaire 
 
X 
 
X 
 
X 
 
 
X 
X 
Sleep diary issuedg 
X 
X 
 
X 
 
X 
 
 
X 
 
Sleep diary collected and reviewed 
 
X 
 
X 
 
X 
 
 
X 
X 
BASC-3 Parenting Relationship Questionnaire 
X 
X 
 
X 
 
X 
 
 
X 
 
Parent Global Impressions-Severity 
X 
X 
 
X 
 
X 
 
 
X 
X 
Parent Global Impressions -Improvement 
 
 
 
X 
 
X 
 
 
X 
X 
Pediatric Quality of Life Inventory 
 
X 
 
 
 
X 
 
 
X 
X 
Clinician-Completed Measures 
 
 
 
 
 
 
 
 
 
 
Pediatric Sleep CGI structured sleep history 
Xh 
Xi 
 
Xi 
 
Xi 
 
 
Xi 
Xi 
Pediatric Sleep CGI-Severity 
X 
X 
 
X 
 
X 
 
 
X 
X 
Pediatric Sleep CGI-Improvement 
 
X 
 
X 
 
X 
 
 
X 
X 
Caregiver top 3 concerns visual analog scale 
 
X 
 
X 
 
X 
 
 
X 
X 
Vineland Adaptive Behavior Scale, 3rd Edition  
X 
 
 
 
X 
 
 
X 
 
CGI-Severity 
X 
X 
 
X 
 
X 
 
 
X 
X 
CGI-Improvement 
 
 
 
X 
 
X 
 
 
X 
X 
Subject-Completed Measures 
 
 
 
 
 
 
 
 
 
 
Actigraph issued 
X 
X 
 
X 
 
X 
 
 
X 
 
Actigraph and actigraphy data collectedj 
 
X 
 
X 
 
X 
 
 
X 
X 


Ovid Therapeutics Inc. 
OV101-17-001 
Statistical Analysis Plan, Version 3.0 
Date Issued: 06MAR2020 
 
 
KiTAP 
X 
X 
 
 
 
X 
 
 
X 
X 
RBANS 
X 
X 
 
 
 
X 
 
 
X 
X 
Evoked response potential (optional) 
 
X 
 
 
 
X 
 
 
X 
 
Abbreviations: BASC-3, Behavior Assessment System for Children, 3rd Edition; CGI, clinical global impressions; DSM-V, Diagnostic and Statistical Manual of Mental 
Disorders; 
EOS, end of study; EOT, end of treatment; FXS, fragile X syndrome; KiTAP, Test of Attentional Performance for Children; LF, long form; PK, pharmacokinetic; RBANS, 
Repeatable Battery for the Assessment of Neuropsychological Status; SF, short form.  
Note: At the investigator’s discretion, subjects may be evaluated at unscheduled clinic visits for reasons related to subject safety. At unscheduled visits, subjects will be 
queried 
about AEs, changes in concomitant medications, and suicidality, and safety laboratory assessments may be conducted. 
a Screening is to be conducted for up to 21 days (inclusive) before Day 1; subjects who meet all entry criteria can be randomly assigned at any time during the screening 
period.  
b There is no Day 0. The screening period can start up to 21 days before Day 1. 
c The EOS visit may occur 4 to 6 weeks after the EOT visit, between the end of Week 16 and the end of Week 18 for subjects who do not stop treatment early. 
d Signs and symptoms of FXS. 
e Only if no written evidence for molecular diagnosis is available in the subject’s records. 
f If the baseline visit occurs within 10 days of the clinical laboratory tests during screening, clinical laboratory testing does not need to be performed at the baseline visit. 
g The sleep diary is to be completed over the 7-day periods immediately preceding Day 1 and the Week 2, Week 6, EOT, and EOS clinic visits; a calendar will be issued to 
ensure that the diary information collection starts on the appropriate days. 
h At the initial screening visit, the clinician will complete parts A, B, and C of the structured sleep history form. 
i At clinic visits after the screening visit, the clinician will complete only part A of the structured sleep history form. 
j The actigraph is to be worn and actigraphy data are to be collected for the 7-day periods immediately preceding Day 1 and the Week 2, Week 6, EOT, and EOS clinic visits; a 
calendar will be issued to ensure that the subject starts wearing the actigraph on the appropriate days.