Clinical trial NCT03569631
Conditions: Fragile X Syndrome FXS Fra(X) Syndrome
Keywords: Phosphodiesterase Type 4D PDE4D Cognitive Dysfunction Neurocognitive Disorders Fragile X Syndrome Fragile X FXS Brain Diseases Central Nervous System Diseases Nervous System Diseases Mental Disorders Cognition Disorders Enzyme Inhibitors Nootropic Agents Developmental Disorder Autism Autistic Spectrum Disorder Genetic Disease Behavioral Disorder Learning Disorder
Sponsor: Tetra Discovery Partners
Start date: 2018-07-09; Completion date: 2020-07-31
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a single-center, randomized, double-blind, 2-period crossover study to explore the effects of BPN14770 on cognitive function and behavior in subjects with Fragile X Syndrome. Subjects will receive both active treatment with BPN14770 capsules and matching placebo capsules in the course of the study. One treatment will be administered during each of the 12-week study periods.

Detailed description:
A total of 30 subjects will be enrolled. The study consists of a screening period of up to 28 days prior to initial treatment, followed by two double-blind treatment periods, each 12 weeks long. A final follow-up visit or phone contact for safety is planned one week after the conclusion of Period 2.

Eligible subjects will be randomized in a blinded, balanced (1:1) fashion to receive either 25 mg BPN14770 capsules or matching placebo capsules during Period 1, followed by the opposite treatment during Period 2. One capsule will be taken twice daily during both double-blind periods.

Subjects will return to the clinic at the end of Weeks 2, 6, and 12 of each study period. Cognitive and behavioral evaluations will be repeated at Weeks 6 and 12 of each Period. Additionally, patients will be monitored for adverse events via a telephone call at the end of Week 1 of each Period, and one week following completion of Period 2 or following early discontinuation.

During clinic visits, adverse effects will be assessed, and laboratory measures, vital signs, and ECGs will be performed. Suicidality risk will also be evaluated at each clinic visit; if a concern is detected, the subject will be referred for further evaluation and treatment. Cognitive and behavioral assessments will be performed during each clinic visit. Pharmacodynamic measures of CNS function will be obtained to evaluated effects of the drug in the brain. Pharmacokinetic samples will be collected to confirm that study drug is present and to estimate plasma exposure at Week 12 of each Period.

Arms: arm 1: 25mg BPN14770 capsules, one capsule taken twice daily for 12 weeks arm 2: Matching placebo capsules, one capsule taken twice daily for 12 weeks
Interventions: intervention 1: BPN14770 intervention 2: Placebo
Intervention descriptions: intervention 1: 25 mg BPN14770 capsules intervention 2: Placebo capsules to mimic 25 mg BPN14770 capsules

Protocol documents:
Prot_000.pdf: 
BPN14770 
Tetra Discove1y Partners Inc. 
Clinical Study Repo11: BPN14770-CNS-203 
Title 
Clinical Trial Protocol: BPN14770-CNS-203 
A Randomized, Double-blind, Placebo-
controlled, 2-period Crossover 
Study ofBPN14770 in Adult Males with 
Fragile X Syndrome 
Substance Identifier 
BPN14770 
IND Number 
Indication 
Phase 
Sponsor 
Sponsor Contact 
127905 
Cognitive Enhancement 
Phase 2 
Tetra Discovery Pa11ners, Inc. 
 
 
Tetra Discovery Pai1ners, Inc. 
38 Fulton Street West Suite 303 
Grand Rapids, MI 49503-2684 
Principal Investigator 
TBD 
Amendment 
Revision Date 
Reason 
NIA 
05 Janmuy 2018 
Original submission 
1 
18 April 2018 
Revisions to address FDA suggestion in May Proceed 
letter 
2 
25 June 2018 
Inclusion of biomarker sample at baseline, clarify 
AE/Medical History pre-dose, typographical 
corrections. 
Confidentiality Statement 
This document contains infonnation that is confidential and proprieta1y to the Sponsor, Tetra Discovery 
Pa1iners, Inc.. This information is being provided to you solely for the pmpose of evaluating and/or 
conducting a clinical trial for the Sponsor. You may disclose the contents of this docU111ent only to 
study personnel under your supervision, the Institutional Review Board, the United States Food and 
Drug Administration, or duly authorized representatives of regulato1y agencies for this purpose under 
the condition that they maintain confidentiality. The contents of this document may not be used in any 
other clinical ttial, disclosed to any other person or entity, and/or published without the p1ior written 
pennission of the Sponsor. The foregoing shall not apply to disclosure required by any regulations; 
however, you will give prompt notice to the Sponsor of any such disclosure. 
Page 1 of 58 
Confidential 
NCT #: NCT03569631


BPN14770 
Tetra Discove1y Partners Inc. 
Clinical Study Repo11: BPN14770-CNS-203 
Protocol: BPN 14 770-CNS-203 
Date: 25 June 20 I 8 
Tetra Discovery Partners, Inc. 
1 
SIGNATURES 
1.1 Sponsor Signatures 
Protocol Number: 
Sponsor: 
Sponsor Contact: 
Study Director & 
Medical Monitor 
Confidential 
BPN 14770-CNS-203 
Tetra Discovery Partners, lnc. 
 
 Tetra Discovery Partners, Inc. 
38 Fulton Street West, Suite 303 
Grand Rapids, MI 4953-2684 
Phone: 
 
 
 Tetra Discovery Partners, Inc. 
38 Fulton Street West, Suite 303 
Grand Rapids, Ml 4953-2684 
Phone: 
 
Page2 of58 
6-27-2018
(Date)
Confidential 


BPN14770 
Clinical Study Repo11: BPN14770-CNS-203 
Protocol: BPNl4770-CNS-203 
Date: 25 June 2018 
1.2 
Investigator Signature 
Tetra Discove1y Partners Inc. 
Tetra Discovery Partners, Inc. 
Confidenti9! 
I confirm that I have read and that I understand this protocol, the Investigator Brochure, and other 
product information provided by the Sponsor. I will provide copies of this protocol and access to all 
information furnished by Tetra Discovery Partners, Inc. to study personnel under my supervision. I 
will discuss this material with them to ensure they are fully informed about the study product and 
study procedures. I will let them know that this information is confidential and proprietary to Tetra 
Discovery Partners, Inc. and that it may not be further disclosed to third parties. 1 understand that the 
study may be terminated or enrollment suspended at any time by Tetra Discovery Partners, Inc. with 
or without cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in accordance with the requirements of this protocol and also protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of 1-lelsinki.1 
• 
International Conference on Harmonization Guidance for Industry, Good Clinical Practice E6.2 
• 
All applicable laws and regulations (21 CFR § 11, 50, 54, 56, and 3 I 2 Subpart D}, including, 
without limitation, data privacy laws and regulations. 
• 
Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
Investigator: 
Confidential 
 
 
Rush University Medical Center 
I 725 W Harrison St. Suite 7 I 8 
Chicago IL, 60612 
 phone 
 fax 
Page 3 of58 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 4 of 58
SYNOPSIS
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
Study Objectives:
In male Fragile X patients aged 18-45 years, inclusive, receiving standard medications:
x
To obtain preliminary assessments of the efficacy of  BPN14770 25 mg bid 
x
To evaluate the safety and tolerability of BPN14770 25 mg
x
To obtain pharmacokinetic, pharmacodynamic and biomarker data on BPN14770 
Exploratory Efficacy Outcome Measures
x
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
x
Test of Attentional Performance (KiTAP)
x
Clinical Global Impression Severity – Investigator rated (CGI-S)
x
Clinical Global Impression Improvement – Investigator rated (CGI-I)
x
Visual Analog Scale (VAS) rating using patient-specific behavioral anchors
x
Aberrant Behavior Checklist (ABC) 
x
Anxiety, Depression, and Mood Scale (ADAMS)
x
Vineland-3 Rating Scale
x
Event-Related Potentials (ERP) 
x
Eye Tracking 
Safety  and Tolerability Endpoints
x
Treatment-emergent Adverse events
x
Changes in vital signs 
x
Clinical laboratory evaluations (chemistry, hematology, urinalysis) 
x
Electrocardiogram (ECG) measurements
Pharmacokinetic Evaluations
x
BPN14770 plasma levels obtained at various time points during the study, according to the Schedule of 
Assessments
Study Design
This is a single-center, Phase 2, randomized, double-blind, placebo-controlled, 2-period crossover study to obtain 
preliminary assessment of the effects of BPN14770 in patients with Fragile X Syndrome. The study will consist of 
a Screening period of up to 28 days prior to initial study drug administration, followed by two 12-week double-
blind treatment periods.  The screening and baseline visits may occur at the same time, provided the results of 
safety labs can be obtained.  No washout period will be utilized between double-blind treatment periods; instead, 
efficacy and biomarker assessments during the second double-blind period (Period 2) will be obtained no sooner 
than Week 6 of Period 2 to allow for drug washout.   A final follow-up visit or phone contact for safety is planned 
one week after the conclusion of Period 2.
Eligible patients will be randomized in a blinded, balanced (1:1) fashion to receive either BPN14770 25mg bid or 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 5 of 58
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
matching placebo during Period 1, followed by the opposite treatment during Period 2.
Brief cognitive and behavioral assessments will be performed during each clinic visit.  Safety and tolerability 
assessments throughout the study will include adverse event monitoring, ECGs, vital signs, blood chemistry, 
hematology, and urinalysis.
Pharmacokinetic and biomarker samples will be collected to at screening and at the end of Period 1 and Period 2. 
The pharmacokinetic samples are primarily to confirm that study drug is present when expected and to estimate 
plasma exposure at end of Periods 1 and 2.
Planned Numbers of Subjects
Enrollment of a total of 30 eligible subjects is planned, 15 per treatment sequence.
Study Duration
The total duration of the study for each subject will be up to 29 weeks, including a maximum of 4-week screening 
period, two 12-week Double-Blind treatment Periods, and a follow-up telephone call approximately 1 week after 
last treatment.
Screen/Enroll
Placebo
BPN14770 
Crossover
n=15
n=15
N=30 subjects
Placebo 
BPN14770
12 Weeks 
Period 2
12 Weeks 
Period 1 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 6 of 58
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
Study Procedures:
The Screening Visit will occur up to 28 days prior to the first study drug administration on Day 1. During 
screening, patients and their parent/legal authorized guardian, if indicated, will review and sign an Informed 
Consent/Assent form prior to any study procedures being performed.  Following confirmation of a prior diagnosis 
for Fragile X, patients will have information collected regarding their neurological and medical/surgical history, 
race/ethnicity, social history (tobacco, alcohol, and/or drug use), and use of prescription and over-the-counter 
medications.  Patients will undergo a full physical exam, have vital signs measured, and 12-lead ECG performed.
Height, weight, and BMI will also be collected.  Fasting blood samples will be collected for chemistry and 
hematology, as well as biomarkers and pharmacokinetics. Urine will be collected for urinalysis.  The Stanford-
Binet test will also be administered at screening, as will an assessment of suicidality risk.
At the Baseline visit (Period 1/Day 1), prior to randomization, patients will receive an abbreviated physical 
examination including vital signs.  However, these will not be repeated if the Screening and Baseline visits occur 
on the same day.  Cognitive and behavioral evaluations will be performed and these measurements will be used as a 
common set of baseline measurements to which post-treatment assessments will be compared for both treatment 
Periods.
During both double-blind periods, patients will receive twice-daily treatment with blinded study medication as 
randomly assigned at baseline.  Doses of study medication should be taken in the morning and at night, at least 6 
hours apart and at least 30 minutes prior to or 1 hour after meals.
Patients will return to the clinic at the end of weeks 2, 6, and 12 of each Period. Cognitive and behavioral 
evaluations will be repeated at Weeks 6 and 12 of each Period, with the exception of ERP and eye tracking which 
will be repeated only at Week 12 of each Period. Additionally, patients will be monitored for adverse events via a 
telephone call at the end of Week 1 of each Period, and one week following completion of Period 2 or following 
early discontinuation.  During clinic visits, adverse effects will be assessed, and laboratory measures, vital signs, 
and ECG will be repeated according to the Schedule of Assessments. Suicidality risk with also be evaluated during 
the treatment periods per the Schedule of Assessments; if a concern is detected, the subject will be referred for 
further evaluation and treatment.
Subject Inclusion/Exclusion Criteria:
Individuals are eligible for the study if they meet all of the Inclusion and none of the Exclusion criteria.  The 
criteria below will be assessed during Screening, which will be up to 28 days prior to first study drug 
administration.  Continued subject eligibility will be verified on Baseline Day 1.
Subject Inclusion Criteria  
1.
Subject is male aged 18 to 45 years, inclusive.
2.
Subject has Fragile X Syndrome with a molecular genetic confirmation of the full Fragile X Mental
5HWDUGDWLRQ )05 PXWDWLRQ  &** UHSHWLWLRQV
3.
Current treatment with no more than 3 prescribed psychotropic medications. Anti-epileptic medications
are permitted and are not counted as psychotropic medications if they are used for treatment of seizures.
Anti-epileptics for other indications, such as the treatment of mood disorders, count towards the limit of
permitted medications.
4.
Permitted concomitant psychotropic medications must be at a stable dose and dosing regimen for at
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 7 of 58
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
least 2 weeks prior to Screening and must remain stable during the period between Screening and the 
commencement of study medication.
5.
Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks prior to Screening
and must remain stable during the period between Screening and the commencement of study
medication.
6.
Subjects with a history of seizure disorder who are currently receiving treatment with anti-epileptics
must have been seizure-free for 3 months preceding Screening, or must be seizure-free for 3 years if not
currently receiving anti-epileptics.
7.
Behavioral and therapy treatments/interventions must be stable for 4 weeks prior to Screening and must
remain stable during the period between Screening and the commencement of study medication, and
throughout the study. Minor changes in hours or times of therapy that are not considered clinically
significant will not be exclusionary. Changes in therapies provided through a school program, due to
school vacations, are allowed.
8.
Subject must be willing to practice barrier methods of contraception while on study, if sexually active.
Abstinence is also considered a reasonable form of birth control in this study population.
9.
Subject has a parent, legal authorized guardian or consistent caregiver.
10. Subject and caregiver are able to attend the clinic regularly and reliably.
11. Subject is able to swallow tablets and capsules.
12. For subjects who are not their own legal guardian, subject's parent/legal authorized guardian is able to
understand and sign an informed consent form to participate in the study.
13. If subject is his/her own legal guardian, he/she can understand and sign informed consent to participate
in the study.
14. If subject is not their own legal guardian, the subject provides assent for participation in the study, if the
subject has the cognitive ability to provide assent.
Subject Exclusion Criteria
1.
History of, or current cardiovascular, renal, hepatic, respiratory, gastrointestinal, psychiatric, neurologic,
cerebrovascular, or other systemic disease that would place the subject at risk or potentially interfere
with the interpretation of the safety, tolerability, or efficacy of the study medication.
Common diseases such as mild hypertension, well-controlled type 2 diabetes mellitus (hemoglobin A1C
[Hgb A1C] <6.5%), etc. are allowed per the investigator's judgment as long as they are stable and
controlled by medical therapy that is constant for at least 4 weeks before randomization.
2.
Renal  impairment, defined as serum creatinine > 1.25 x ULN at screening
3.
Hepatic impairment, defined as ALT or AST elevation > 2 x ULN at screening.  Note:  LFTs may be
repeated after 1 week to evaluate return to acceptable limits; if LFTs remain elevated, subject is
ineligible to participate.
4.
Clinically significant abnormalities, in the investigator's judgment, in safety laboratory tests, vital signs,
or ECG, as measured during Screening.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 8 of 58
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
5.
History of substance abuse within the past year, according to investigator assessment.
6.
Significant hearing or visual impairment that may affect the subject's ability to complete the test
procedures.
7.
Concurrent major psychiatric condition (e.g., Major Depressive Disorder, Schizophrenia or Bipolar
Disorder) as diagnosed by the investigator. Subjects with additional diagnosis of Autism Spectrum
Disorder or Anxiety Disorder will be allowed.
8.
Subject has active diseases that would interfere with participation, such as acquired immunodeficiency
disorder, hepatitis C, hepatitis B, or tuberculosis.
9.
Subject is planning to commence psychotherapy or cognitive behavior therapy (CBT) during the period
of the study or had begun psychotherapy or CBT within 4 weeks prior to Screening.
10. Subject is related to anyone employed by the sponsor, investigator, or study staff.
11. Subject has BMI less than 18 or greater than 36.
12. Subject has participated in another clinical trial within the 30 days preceding Screening.
Investigational Product, Dosage, and Mode of Administration:  
In this randomized double-blind, placebo-controlled, 2-period cross-over study, 30 patients will be randomized 
(1:1) to receive each of the following two treatments (one during each 12 week treatment Period):
x
BPN14770 25 mg bid
x
Matching Placebo
All study medications will be provided as identical-appearing HPMC capsules in HPE bottles.  One capsule is to be 
taken orally in the morning, and one capsule is to be taken orally at night, with at least 120 mL (4 ounces) of liquid.  
Doses should be taken at least 6 hours apart, and at least 30 minutes prior to or 1 hour after meals.
Overview of Endpoints
Exploratory Efficacy Outcome Measures
x
NIH-TCB: Cognitive battery assessing cognition, administered using an iPad
x
KiTAP: Computerized executive battery with assessments of alertness (reaction time), distractibility, go/nogo 
(impulsiveness), and flexibility 
x
Clinical Global Impression Severity – Investigator rated (CGI-S) Standardized ranking scale with 7 rankings
x
Clinical Global Impression Improvement – Investigator rated (CGI-I): Standardized ranking scale with 7 
rankings
x
Visual Analog Scale (VAS) – Parent/caregiver-rated assessment of patient-specific behavioral anchors:
Domains of daily functioning, anxiety/irritability and language.  
x
ABC: Parent/caregiver-rated scale with six subscales to assess irritability, social avoidance, lethargy, 
hyperactivity, inappropriate speech and social avoidance, using ABC-FX factoring system.
x
ADAMS:  Parent/caregiver rated scale with a total score and five sub-scores to assess manic/hyperactive 
behavior, depressed mood, social avoidance, general anxiety, and obsessive/compulsive behavior.
x
Vineland-3 Adaptive Behavior Scale: Clinician-administered standardized interview yielding adaptive 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 9 of 58
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
behavior composite score and domain standard scores in domains of: communication (receptive, expressive, 
and written adaptive language functions), daily living skills (personal, domestic, and community skills), 
socialization (interpersonal relationships, play and leisure time, and coping abilities), and motor skills (gross 
and fine motor skills).
x
Event-Related Potentials (ERP) - Measure of auditory habituation based on EEG signals
x
Eye Tracking – Measure of gaze aversion (social anxiety) and pupilometry (autonomic function)
Safety and Tolerability: The safety variables to be assessed include adverse events; clinical laboratory parameters 
(chemistry, hematology, and urinalysis); 12-lead electrocardiograms (ECGs); physical examinations; and vital signs 
(including blood pressure, heart rate, and respiratory rate).
Pharmacokinetics: Plasma BPN14770 concentrations will be obtained at screening and at the final visit during 
each treatment Period.  Samples will be drawn at the time of the clinic visit, with documentation of time of day 
sample was obtained, and time of day of most recent dose of study medication.  
Biomarkers: Pharmacokinetic samples will be retained and may be utilized subsequently for biomarker 
assessment.  
Statistical Considerations
Efficacy Analyses
The primary efficacy population will be the intent to treat (ITT) efficacy population, which will include all 
randomized subjects who received at least one dose of treatment and returned for at least one follow-up visit. The 
completers population (CP), defined as all randomized subjects who complete both treatment periods with no 
significant protocol violations, will be used to evaluate the robustness of the ITT results.
All efficacy parameters will be summarized at each time point collected and standard descriptive statistics 
provided. Baseline measurements are defined as those obtained on Day 1/Period 1 prior to receipt of any study 
medication.  For cognitive parameters measured at baseline, change from baseline will also be calculated and 
standard descriptive statistics provided for each time point. Linear mixed models will be used to explore potential 
treatment effects. 
Safety Analyses
The Safety population will include all randomized subjects who received at least one dose of study treatment. 
Adverse Events (AEs), including clinically meaningful laboratory abnormalities and significant behavioral changes.
AE severity and relatedness to treatment will be assessed. AEs will be tabulated for placebo and BPN14770 
treatments. Summaries will also be provided by severity and relationship to treatment. Serious Adverse Events 
(SAEs) will be summarized separately, in a manner similar to that used for Adverse Events.
Sample Size Determination
Given the exploratory nature of this study, a definitive sample size calculation is not possible. However, for the 
sake of providing an evaluation of the potential power to detect a meaningful difference between treatments, a 
crossover study having no carryover effects with 80% power, a 5% alpha level, and a common standard deviation 
of 3 units, a sample size of 30 evaluable patients (15 per sequence group) will allow detection of an effect size of 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 10 of 58
Name of Sponsor/Company:
Tetra Discovery Partners, Inc.
Name of Investigational Product:
BPN14770
Study Title:  
A Randomized, Double-blind, Placebo-controlled, 2-period 
Crossover Study of BPN14770 in Adult Males with Fragile X
Syndrome
Study Number:
BPN14770-CNS-203
Study Phase:
Phase 2
approximately 2.25 units on the ABC Total Score outcome measure. If carryover effects or excessive dropouts 
allow only for a first Period analysis, a sample size of 15 per group during the first period would allow for detection 
of an effect size of 3.19 units.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
__________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
Confidential
Page 11 of 58
2
TABLE OF CONTENTS
1 
SIGNATURES
2 
1.1 
Sponsor Signatures
2 
1.2 
Investigator Signature
3 
2 
TABLE OF CONTENTS
11 
3 
LIST OF ABBREVIATIONS
15 
4 
INTRODUCTION
18 
4.1 
Background
18 
4.2 
Rationale
18 
4.3 
Risk/Benefit
19 
4.3.1 
Preclinical Pharmacology
19 
4.3.2 
Clinical Experience
20 
4.3.2.1 
BPN14770-CNS-101
20 
4.3.2.2 
BPN14770-CNS-102
20 
4.3.2.3 
BPN14770-CNS-103
21 
4.4 
Study Objectives and Endpoints
22 
4.4.1 
Study Objectives
22 
4.4.2 
Exploratory Efficacy Outcome Measures
22 
4.4.3 
Safety and Tolerability Endpoints
22 
4.4.4 
Pharmacokinetic Endpoints
23 
4.4.5 
Biomarkers
23 
5 
INVESTIGATIONAL PLAN
23 
5.1 
Overall Study Design
23 
5.1.1 
Dose Selection
24 
5.2 
Study Duration
24 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS
24 
6.1 
Study Population
24 
6.2 
Subject Inclusion Criteria
24 
6.3 
Subject Exclusion Criteria
25 
6.4 
Subject Withdrawal
26 
6.5 
Replacement of Subjects
27 
7 
TREATMENT OF SUBJECTS
27 
7.1 
Treatment Arms
27 
7.2 
Study Medications
27 
7.3 
Drug Accountability
28 
7.4 
Blinding
28 
7.5 
Assignment of Subjects to Treatment Arms
28 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
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Page 12 of 58
7.6 
Study Drug Administration
29 
7.7 
Prior and Concomitant Medications
29 
7.8 
Other Therapeutic Treatments
29 
7.9 
Dietary Guidelines
29 
7.10 
Lifestyle Guidelines
29 
8 
STUDY PROCEDURES AND ASSESSMENTS
29 
8.1 
Informed Consent
29 
8.2 
Medical /Surgical History
30 
8.3 
Demographics and Social History
30 
8.4 
Stanford Binet Intelligence Scale
30 
8.5 
Physical Examination (Full and Abbreviated)
30 
8.6 
Height, Weight, Body Mass Index
31 
8.7 
Vital Signs
31 
8.8 
Electrocardiograms
31 
8.9 
Laboratory Assessments
31 
8.10 
Management of Abnormal Clinical Laboratory Tests
32 
8.11 
Suicidality Assessment
32 
8.12 
Additional Safety Measures
32 
8.13 
Exploratory Efficacy Assessments
32 
8.13.1 
Descriptions of Efficacy Assessment Instruments
32 
8.13.1.1 
NIH-TCB
33 
8.13.1.2 
Test of Attentional Performance (KiTAP)
33 
8.13.1.3 
Clinical Global Impression
33 
8.13.1.4 
VAS Rating Scale
34 
8.13.1.5 
Aberrant Behavior Checklist (ABC)
34 
8.13.1.6 
Anxiety Depression and Mood Scale (ADAMS)
35 
8.13.1.7 
Vineland-3 Rating Scale
35 
8.13.1.8 
Event-Related Potentials (ERP)
35 
8.13.1.9 
Eye Tracking
36 
8.13.2 
Timing of Efficacy Assessments
36 
8.13.2.1 
Baseline (Period 1/Day 1)
36 
8.13.2.2 
Week 6 (Periods 1 and 2)
36 
8.13.2.3 
Week 12 (Periods 1 and 2)
36 
8.14 
Pharmacokinetic Assessment
37 
8.14.1 
Plasma Pharmacokinetic Samples
37 
8.14.2 
Processing and Shipment of Pharmacokinetic Samples
37 
8.14.3 
Analytical Method
38 
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8.14.4 
Plasma Pharmacokinetic Parameters
38 
8.15 
Biomarker Assessments
38 
9 
EVALUATION AND REPORTING OF ADVERSE EVENTS
38 
9.1 
Adverse Events
38 
9.2 
Definitions
39 
9.2.1 
Adverse Drug Reaction
39 
9.2.2 
Unexpected Adverse Event/ Unexpected Adverse Drug Reaction
39 
9.2.3 
Serious Adverse Events
39 
9.3 
Assessment of Adverse Events by the Investigator
40 
9.3.1 
Causality/Relatedness
40 
9.3.2 
Severity
41 
9.3.3 
Adverse Event Monitoring and Follow-up
41 
9.3.4 
Reporting Serious Adverse Events
42 
10 STUDY PROCEDURES AND ASSESSMENTS BY VISIT
43 
10.1 
Schedule of Assessments
43 
10.2 
Screening (Day -28 to Day -1)
43 
10.3 
Baseline (Period 1/Day 1)
43 
10.3.1 
Prior to Randomization
44 
10.3.2 
Week 1 (Periods 1 and 2)
44 
10.3.3 
Week 2 (Periods 1 and 2)
44 
10.3.4 
Week 6 (Periods 1 and 2)
45 
10.3.5 
Week 12 (Periods 1 and 2)
45 
10.3.6 
Week 13 (Period 2, Final Contact at End of Study)
46 
10.3.7 
Early Termination
46 
11 PLANNED STATISTICAL METHODS
47 
11.1 
Sample Size
47 
11.2 
Demographics
47 
11.3 
Analysis Populations
47 
11.4 
Efficacy: Cognitive Testing Analysis
47 
11.5 
Safety Analysis
48 
11.6 
Pharmacokinetic Analysis
48 
11.7 
Biomarker Analysis
48 
12 DATA MANAGEMENT
48 
12.1 
Data Handling
48 
12.2 
Computer Systems
48 
12.3 
Data Entry
48 
12.4 
Data Validation
49 
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13 INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL
49 
13.1 
Ethical Conduct of the Study
49 
13.2 
Institutional Review Board (IRB)
49 
13.3 
Informed Consent
50 
13.4 
Study Monitoring
50 
13.5 
Disclosure of Information
51 
13.6 
Record Storage and Retention
51 
13.7 
Protocol Amendments and Deviations
52 
13.8 
Access to Source Documentation
52 
13.9 
Financial Disclosure
52 
13.10 Publication Policy
52 
14 ADMINISTRATIVE INFORMATION
53 
14.1 
Sponsor
53 
14.2 
Biological Specimens
53 
15 REFERENCES
54 
16 APPENDICES
56 
16.1 
Schedule of Assessments
56 
16.2 
Clinical Laboratory Analytes
58 
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3
LIST OF ABBREVIATIONS 
ABC (-FX)
Aberrant Behavior Checklist (Fragile X specific factoring system)
ADAMS
Anxiety, Depression, and Mood Scale
AE(s)
Adverse event(s)
ADR
Adverse drug reaction
ALT
Alanine transaminase
API
Active pharmaceutical ingredient
bid
Twice daily
BMI
Body mass index
BP
Blood pressure
BPM
Beats per minute
BUN
Blood urea nitrogen
°C
Degrees centigrade
cAMP
3’-5’- cyclic adenosine monophosphate
CBT
Cognitive Behavioral Therapy
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating – Sum of Boxes
CFR
Code of Federal Regulations
CGI-I
Clinical Global Impression Improvement – Investigator rated
CGG
CGG trinucleotide repeating codon
CGI-S
Clinical Global Impression Severity – Investigator rated
Cmax
Maximum plasma concentration
CNS
Central nervous system
CP
Completers population
CREB
cAMP response element binding
CRF
Case report form
DCCS
Dimensional change card sort (test)
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EEG
Electroencephalogram
EH
Extraction ratio
ERP
Event-Related Potentials
FDA
Food and Drug Administration
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FMR1
Fragile X mental retardation
FXS
Fragile X Syndrome
gm
Gram
GCP
Good Clinical Practice
GI
gastrointestinal
hERG
human Ether-à-go-go-Related Gene
HDPE
High density polyethylene
HgbA1C
Hemoglobin A1C
HPMC
Hydroxypropyl methylcellulose
ICF
Informed consent form
ICH
International Conference on Harmonization 
IND
Investigational New Drug 
IRB
Institutional Review Board
ITI
Inter-trial interval
ITT
Intent to treat (population)
kg
kilogram
KiTAP
Test of Attentional Performance
MAD
Multiple ascending dose
MED
Minimum effective dose
mg
Milligram
mL
Milliliter
msec
Millisecond
MTD
Maximum tolerated dose
NAM
Negative allosteric modulator
μ
Micro
ng
Nanogram
NIH-TCB
NIH Toolbox Cognitive Battery for Intellectual Disabilities
NOAEL
No observed adverse effect level
PDE4
phosphodiesterase type-4
PDE4D
phosphodiesterase type-4 subtype D
PDE4D-NAM
phosphodiesterase type-4D-negative allosteric modulator
PK
Pharmacokinetic
PO
By mouth (per os)
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QD
Once daily
QTc
CRUUHFWHG 47 LQWHUYDO
RBC
Red blood cell
ROI
Region of interest
SAD
Single ascending dose
SAE
Serious adverse event
SD
Standard deviation
SOP
Standard operating procedure
Tmax
Time to maximum concentration
VAS
Visual analog scale
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4
INTRODUCTION
4.1
Background
Tetra Discovery Partners, Inc. is a central nervous system (CNS) biotechnology company that 
uses structure-based drug design to discover negative allosteric modulators (NAMs) of 
phosphodiesterase-4 (PDE4) subtypes for neurological and psychiatric diseases.
Tetra has developed a mechanistically novel class of drugs to address cognitive impairment 
across multiple psychiatric and neurological indications.
These new drugs selectively target 
subtypes of phosphodiesterase type-4D (PDE4D).3,4 The PDE4D enzyme subtype is a highly 
validated CNS target for improving cognition.
4.2
Rationale
Fragile X syndrome (FXS) is a disorder in which affected individuals display intellectual 
disability as well as symptoms typical of autism spectrum disorder, due to silencing of the X-
linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a 
consistent finding in patients and in preclinical models of FXS. BPN14770, a prototypic 
phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) Daily treatment of adult 
male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved 
social interaction, and improved natural behaviors such as nesting and marble burying as well as 
dendritic spine morphology. There was no decrement in behavioral scores in control mice treated 
with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the 
drug. Thus, BPN14770 may be useful for the treatment of FXS with potential expansion to the 
treatment of autism spectrum disorder.5
A total of 136 subjects have received BPN14770 either as a single dose or as a multiple dose 
regimen.  Of these subjects, 106 (78%) were d 55 years of age and 30 (22 ZHUH  \HDUV RI
age.
The single dose escalation study (-101) in 24 subjects d 55years of age determined that a single
100mg dose was the maximum tolerated dose of BPN14770, based on the occurrence of nausea 
and vomiting in the majority of subjects at this dose. There were no notable adverse events in 
other body systems, no observed changes in vital signs or electrocardiogram, no adverse 
laboratory findings, and no serious adverse events were recorded. The multiple dose escalation 
study assessed 15 mg, 30 mg, and 50 mg doses given BID to 18 subjects d45 years of age and 
doses of 10 mg, 20 mg, and 40 mg given BID to 30 subjects  60 years of age.  All of these 
doses were well tolerated.  An additional cohort of 6 subjects d45 years of age received 75mg 
once daily in order to compare the safety and PK profiles to the 100mg MTD determined in the 
single dose study. The 75 mg dose was associated with GI adverse experiences, confirming the 
findings at 100 mg in the single ascending dose study.  The BPN14770 doses assessed in the 
scopolamine challenge study were 10 mg and 50 mg QD. Of the 38 subjects enrolled, 37 
received at least one of the two doses of BPN14770; one subject withdrew from the crossover 
study prior to a dosing cohort containing BPN14770. 
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In the multiple ascending dose study (-102), BPN14770 administered twice daily to healthy 
elderly subjects was associated with improvement in complex attention/working memory, 
delayed recall of verbal information, and delayed recall of visual information (10 and 20 mg 
doses). No beneficial or detrimental effects were observed on other cognitive tasks studied. The 
40-mg BID dose was not associated with improvement in any cognitive domain, possibly
because of a higher frequency of adverse events, primarily headaches, at this dose level.
Therefore, a daily dose of 25 mg bid was chosen for this clinical study in FXS.
4.3
Risk/Benefit
4.3.1
Preclinical Pharmacology
BPN14770 is a first-in-class, subtype selective, phosphodiesterase type-4D-negative allosteric 
modulator (PDE4D-NAM).  The unique mechanism of action and subtype selectivity 
distinguishes BPN14770 from the two approved PDE4 inhibitors, roflumilast (Daliresp™) and 
apremilast (Otezla™).  BPN14770 does not bind to the active site of the PDE4 enzyme and,
unlike roflumilast and apremilast, does not cause emesis in ferrets, cynomolgous monkeys or 
marmosets; furthermore, it has not been found to cause mesenteric vasculopathy in rats or dogs 
in toxicological studies of 3 months duration.  Thus, BPN14770 presents a unique procognitive 
and preclinical safety profile.  
Clearance of BPN14770 by hepatocytes from human, rat, dog and monkey, expressed as hepatic 
extraction ratio (EH), was 16%, 8.2%, 17%, and 12%, respectively.  Qualitative metabolite 
profiling in human, rat, dog, and monkey hepatocytes showed a single metabolite in human 
(<1% parent).  BPN14770 was highly bound to plasma proteins in all species tested.  The 
fraction unbound (free) was 0.5, 0.4, 0.2, and 0.5%, for mouse, rat, dog, and human, respectively.  
BPN14770 is highly bioavailable in rats, mice and dogs (F% = 100), distributes to brain (B/P = 
0.32-0.48), and has a plasma t½ of 4.8 hours in rats, 10.9 hours in mice, and 11 hours in dogs. 
The multi-species pharmacokinetic data suggest that BPN14770 will have adequate half-life for 
once daily oral administration in humans.  In bile duct cannulated rats, BPN14770 was 
eliminated as a conjugate through the bile.  Only the unchanged drug was detected in plasma, 
and no BPN14770 was detected in urine.  
BPN14770 did not affect cardiovascular function in beagle dogs at doses up to 100 mg/kg, nor 
did the compound affect respiratory function or exert neuropharmacologic effects in rats at doses 
up to 60 mg/kg.  In the in vitro human Ether-à-go-go-Related Gene (hERG) assay, an increase in 
current of 12% and 33% was seen at concentrations of 10 and 30 μM, respectively.  No IC50
could be calculated due to this minor increase in current.
In rat toxicology studies of 28-days and 13-weeks, BPN14770 was well tolerated up to 60 mg/kg 
with no deaths on study, and no adverse hematology, clinical chemistry, liver weight or gross 
necropsy findings. There were no microscopic findings. Unlike the PDE4 inhibitors roflumilast 
and apremilast, BPN14770 did not cause mesenteric vasculopathy at the doses studied.  
In dog toxicology studies of 28-days and 13-weeks, the no observed adverse effect level 
(NOAEL) for BPN14770 was 30 mg/kg. At 100 mg/kg in the 28-day study, BPN14770 caused 
inappetance and weight loss and in female dogs an approximately 30 msec increase in QTc with 
a concomitant increase in heart rate of 10 bpm. There were no changes in hematology or 
ophthalmology. Macroscopic observations included pale livers in two of eight animals at 100 
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mg/kg which correlated with mild alanine transaminase (ALT) elevation only in those two 
animals. Microscopic changes of periportal hepatocellular cytoplasmic vacuolation were 
observed in the livers of one male and two female dogs at 100 mg/kg. No liver changes were 
observed in recovery dogs suggesting that these changes, if present, were reversible.
4.3.2
Clinical Experience
4.3.2.1
BPN14770-CNS-101
A first-in-human (FIH), single ascending dose (SAD) trial (BPN14770-CNS-101) in 24 healthy 
subjects at doses ranging from 5 mg to 100 mg has been completed. The results from this study 
indicate single doses of BPN14770, in the range of 5 mg to 100 mg, were safe and generally well 
tolerated.  The maximum tolerated dose (MTD) was determined to be 100 mg, after 4 of 6 
subjects in this dose group experienced nausea and, of those, two experienced vomiting.  
The most commonly reported treatment-emergent, drug-related adverse events were nausea and 
vomiting.  No safety signals were noted in the results of the other safety analyses.  No deaths or 
other serious adverse events were reported.  No subjects withdrew from the study due to adverse 
events.
In the SAD trial, detectable plasma BPN14770 concentrations were measured after dosing (at all 
4 dose levels) starting between 0.5 hour and 1 hour after dosing, continuing through at least 48
hours after dosing.  Drug absorption was variable but moderately rapid with median time to 
maximum concentration
(Tmax)
values ranging from 1.5 to 3 hours.  The plasma 
pharmacokinetics of BPN14770 after oral administration appeared to be linear for single doses 
ranging from 5 to 100 mg; although a slight trend for a greater than proportional increase in 
exposure was observed in the 100-mg group as compared to the lower dose groups.
The 
apparent terminal elimination half-life of BPN14770 was consistent among dose groups and 
averaged between 11 and 13 hours. 
Based on the preclinical models, the concentrations 
associated with doses as low as 15 mg were potentially adequate to produce cognitive 
improvement after once- or twice- per day dosing.
4.3.2.2
BPN14770-CNS-102
In the multiple ascending dose (MAD) trial (BPN14770-CNS-102), 76 healthy young and elderly 
subjects were administered multiple doses of BPN14770 twice daily (every 12 hours) for 8 days. 
Young subjects (d45 years; n=18 treated, 7 placebo) received twice-daily doses of 15 mg, 30 mg, 
50 mg or placebo for 8 days.  Elderly subjects ( \HDUV n=30 treated, 15 placebo) received
twice-daily doses of 10 mg, 20 mg, and 40 mg for 8 days. Twice-daily dosing was selected to 
ensure adequate BPN14770 levels in the brain and plasma throughout the day and night.  An 
additional cohort of 6 young subjects received a once-daily dose of 75 mg for 8 days to obtain 
additional safety and pharmacokinetic (PK) data at a dose level close to the MTD determined in 
the SAD study.
No deaths or serious adverse events were reported, and no subjects in either the young or elderly 
cohorts withdrew from the study due to adverse events.  All treatment-emergent adverse events 
resolved without sequelae by the follow-up visit. 
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All study-drug related adverse events that occurred in more than 1 young subject were in the 75-
mg QD dose group and consisted of nausea (reported by 4 of 6 subjects, vomiting (reported by 2 
of 6 subjects who also experienced nausea), and decreased appetite (reported by 3 of 6 subjects). 
Across the young subject cohorts, all but 2 of the reported adverse events were mild in severity; 
moderate nausea and vomiting were reported in 1 of 6 subjects (16.7%) in the 75-mg QD dose 
group on Day 2 of multiple dosing. These events were considered by the Investigator as probably 
related to study treatment, resolved without sequelae within 13 hours of onset, and did not recur 
upon subsequent dosing. Among the young subject dose groups, no clinically significant effects 
of multiple oral doses of BPN14770 (15 mg, 30 mg, 50 mg, or 75 mg) were observed on 
biochemistry, hematology, or urinalysis; vital signs; or ECGs. 
Among the elderly subject cohorts, the percentage of subjects who experienced at least one 
treatment-emergent adverse event was similar between the 10-mg BID, 20-mg BID, and placebo 
groups (ranging from 30% to 50%) and was higher for the 40-mg BID dose group (90%). 
Adverse events reported in 2 or more elderly subjects within a dose group were all reported by 
subjects in the 40-mg dose group and consisted of diarrhea, increased alanine and aspartate 
aminotransferase, hot flush (each reported at a frequency rate of 20%) and headache (reported at 
a frequency rate of 40%).  Among the elderly subject dose groups, no clinically significant 
effects of multiple oral doses of BPN14770 (10 mg, 20 mg, or 40 mg) were observed on 
biochemistry, hematology, or urinalysis; vital signs; or ECGs. 
With respect to cognitive testing, BPN14770 10 mg given twice daily was associated with 
improvement in complex attention/working memory and delayed recall of both visual and verbal 
information. Treatment with BPN14770 20 mg twice daily was associated with similar benefits 
as the 10 mg twice daily regimen, excluding improvement in delayed recall of visual 
information. Neither the 10- or 20-mg BID regimens was associated with improvement in 
psychomotor function, visual, or verbal learning, or executive function. The 40-mg BID regimen 
was not associated with improvement in any cognitive domain. 
Pharmacokinetic analyses found that steady-state appeared to be reached after 3 to 4 days of BID 
or QD dosing in both young and elderly subjects. Following BID dosing of BPN14770 in healthy 
young subjects, Cmax and AUC12 appeared to increase in a greater than dose-proportional 
fashion from 15 mg to either 30 mg or 50 mg. A moderate degree of accumulation (up to 
approximately 5-fold) was observed after BID dosing in healthy young subjects, with less 
accumulation (approximately 2-fold) after QD dosing. 
In healthy young subjects, mean peak to trough fluctuation was similar among BID regimens, 
ranging from 171% to 179%, and was 337% for the QD regimen.  In healthy elderly subjects, 
mean peak to trough fluctuation was similar among BID regimens, ranging from 156% to 249%. 
4.3.2.3
BPN14770-CNS-103
The third Phase 1 trial of BPN14770 (BPN14770-CNS-103) was a randomized, double-blind, 
placebo-controlled, 6-period crossover study to evaluate the effects of BPN14770 10 and 50 mg 
in reversing scopolamine-induced cognitive impairment in healthy volunteers. A positive control, 
donepezil 10 mg, was included, and additivity of BPN14770 50 mg to donepezil 10 mg in 
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reversing scopolamine effects was also evaluated. A total of 38 subjects were enrolled into the 
study. 
The Cogstate Computerized Battery Test results suggest that, as expected, a 0.5 mg dose of 
scopolamine induced a decline in cognitive function, while a 10-mg dose of donepezil 
ameliorated this decline. Doses of 10 or 50 mg of BPN14770 did not produce a systematic 
reversal of the scopolamine-induced cognitive decline, administered alone or with a 10-mg dose 
of donepezil.
BPN14770 was safe and generally well tolerated when administered with scopolamine
in healthy subjects. The incidence of nausea and vomiting increased several fold when either 
BPN14770 50 mg or donepezil was administered with scopolamine, or when both BPN14770 
and donepezil were administered with scopolamine, compared to BPN14770 10 mg, placebo, or 
scopolamine alone. 
4.4
Study Objectives and Endpoints
4.4.1
Study Objectives
In male Fragile X patients aged 18-45 years, inclusive, receiving standard medications: 
x
To obtain a preliminary assessment of the efficacy of  BPN14770 25 mg bid 
x
To evaluate the safety and tolerability of BPN14770 25 mg
x
To obtain pharmacokinetic, pharmacodynamic, and biomarker data on BPN14770
4.4.2
Exploratory Efficacy Outcome Measures
The following instruments will be used to assess the exploratory efficacy endpoints: 
x
NIH Toolbox Cognitive Battery Modified for Intellectual Disabilities (NIH-TCB)
x
Test of Attentional Performance (KiTAP)
x
Clinical Global Impression Severity – Investigator rated (CGI-S)
x
Clinical Global Impression Improvement – Investigator rated (CGI-I)
x
VAS Rating Scale using patient-specific behavioral anchors
x
Aberrant Behavior Checklist (ABC) 
x
Anxiety, Depression, and Mood Scale (ADAMS)
x
Vineland-3 Rating Scale
x
Event-Related Potentials (ERP) 
x
Eye Tracking 
4.4.3
Safety and Tolerability Endpoints
The following safety assessments will be conducted during the study.
x
Treatment-emergent Adverse events 
x
Changes in vital signs 
x
Clinical laboratory evaluations (chemistry, hematology, urinalysis) 
x
Changes in electrocardiogram (ECG) measurements
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4.4.4
Pharmacokinetic Endpoints
Plasma BPN14770 concentrations will be measured to verify that study drug is present when 
expected and to estimate plasma exposure after 12 weeks of treatment.
4.4.5
Biomarkers
Retained plasma samples may be used to explore biomarkers potentially associated with FXS.
5
INVESTIGATIONAL PLAN
5.1
Overall Study Design
This is a single center, Phase 2, randomized, double-blind, placebo-controlled, 2-period 
crossover study to obtain preliminary assessment of the effects of BPN14770 in patients with 
Fragile X Syndrome. As schematic display of the study design is shown in Figure 1.
The study will consist of a Screening period of up to 28 days prior to initial study drug 
administration, followed by two 12-week double-blind treatment periods.  The screening and 
baseline visits may occur at the same time, provided the results of safety labs can be obtained.  
No washout period will be utilized between double-blind treatment periods; instead, efficacy and 
biomarker assessments during the second double-blind period (Period 2) will be obtained after a 
minimum of 6 weeks to allow for drug washout.   A final follow-up phone contact for safety is 
planned one week after the conclusion of Period 2.
Eligible patients will be randomized in a blinded, balanced (1:1) fashion to receive either 
BPN14770 25mg bid or matching placebo during Period 1, followed by the opposite treatment 
during Period 2.
Brief cognitive and behavioral assessments will be performed during each clinic visit.  Safety 
and tolerability assessments throughout the study will include adverse event monitoring, ECGs, 
vital signs, blood chemistry, hematology, and urinalysis.  
Pharmacokinetic samples will be collected at screening and at end of Periods 1 and 2 (Week 12to 
confirm that study drug is present when expected and to estimate plasma exposure.). Biomarker 
samples will be collected at the time the pharmacokinetics samples are obtained.
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Figure 1
Study Design Schematic
5.1.1
Dose Selection
The dose of 25 mg BPN14770 to be taken twice daily was chosen for testing in this study.  
Based on pharmacokinetic data from study BPN14770-CNS-102 (MAD), average plasma 
concentrations of BPH14770 at 10 mg dosing are projected to be approximately 60 ng/ml. 
Therefore, the lower dose of 10 mg has the potential to demonstrate efficacy in this study, 
although given the uncertainties of translation from preclinical models, it may be below the 
effective range. On the other hand, the 25 mg dose should be above that needed for efficacy, 
with projected average plasma concentrations over 200 ng/ml. The twice-daily dose of 25mg 
selected for this study falls well within the tolerance limits defined by the SAD and MAD 
studies, as noted above.
5.2
Study Duration
The total duration of the study for each subject will be up to 29 weeks, including a maximum of 
a 4-week screening period, two 12-week double-blind Treatment Periods, and a follow-up call 
approximately 1 week after last treatment.
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Study Population
Individuals are eligible for the study if they meet all of the inclusion and none of the exclusion 
criteria. The criteria below will be assessed at the Screening visit which should within 28 days 
prior to first study drug administration. The Screening and Baseline Visits may be combined if
site procedures allow.
6.2
Subject Inclusion Criteria
1. Subject is male aged 18 to 45 years, inclusive.
Screen/Enroll
Placebo
BPN14770 
Crossover
n=15
n=15
N=30 subjects
Placebo 
BPN14770
12 Weeks 
Period 2
12 Weeks 
Period 1 
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2. Subject has Fragile X Syndrome with a molecular genetic confirmation of the full
Fragile X MHQWDO 5HWDUGDWLRQ )05 PXWDWLRQ  &** UHSHWLWLRQV
3. Current treatment with no more than 3 prescribed psychotropic medications. Anti-
epileptic medications are permitted and are not counted as psychotropic medications if
they are used for treatment of seizures. Anti-epileptics for other indications, such as the
treatment of mood disorders, count towards the limit of permitted medications.
4. Permitted concomitant psychotropic medications must be at a stable dose and dosing
regimen for at least 2 weeks prior to Screening and must remain stable during the
period between Screening and the commencement of study medication.
5. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks
prior to Screening and must remain stable during the period between Screening and the
commencement of study medication.
6. Subjects with a history of seizure disorder who are currently receiving treatment with
anti-epileptics must have been seizure-free for 3 months preceding Screening, or must
be seizure-free for 3 years if not currently receiving anti-epileptics.
7. Behavioral and therapy treatments/interventions must be stable for 4 weeks prior to
Screening and must remain stable during the period between Screening and the
commencement of study medication, and throughout the study. Minor changes in hours
or times of therapy that are not considered clinically significant will not be exclusionary.
Changes in therapies provided through a school program, due to school vacations, are
allowed.
8. Subject must be willing to practice barrier methods of contraception while on study, if
sexually active. Abstinence is also considered a reasonable form of birth control in this
study population.
9. Subject has a parent, legal authorized guardian or consistent caregiver.
10. Subject and caregiver are able to attend the clinic regularly and reliably.
11. Subject is able to swallow tablets and capsules.
12. For subjects who are not their own legal guardian, subject's parent/legal authorized
guardian is able to understand and sign an informed consent form to participate in the
study.
13. If subject is his/her own legal guardian, he/she can understand and sign informed
consent to participate in the study.
14. If subject is not their own legal guardian, the subject provides assent for participation in
the study, if the subject has the cognitive ability to provide assent.
6.3
Subject Exclusion Criteria
The following Exclusions apply to findings during Screening or at Baseline (Day 1):
1. History of, or current cardiovascular, renal, hepatic, respiratory, gastrointestinal,
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psychiatric, neurologic, cerebrovascular, or other systemic disease that would place the 
subject at risk or potentially interfere with the interpretation of the safety, tolerability, 
or efficacy of the study medication.  
Common diseases such as mild hypertension, well-controlled type 2 diabetes mellitus 
(hemoglobin A1C [HgbA1C] <6.5%), etc. are allowed per the investigator's judgment 
as long as they are stable and controlled by medical therapy that is constant for at least 
4 weeks before randomization.
2. Renal impairment, defined as serum creatinine > 1.25 x ULN at screening.
3. Hepatic impairment, defined as ALT or AST elevation > 2 x ULN at screening.  Note:
LFTs may be repeated after 1 week to evaluate return to acceptable limits; if LFTs
remain elevated, subject is ineligible to participate.
4. Clinically significant abnormalities, in the investigator's judgment, in safety laboratory
tests, vital signs, or ECG, as measured during Screening.
5. History of substance abuse within the past year, according to investigator assessment.
6. Significant hearing or visual impairment that may affect the subject's ability to
complete the test procedures.
7. Concurrent major psychiatric condition (e.g., Major Depressive Disorder,
Schizophrenia or Bipolar Disorder) as diagnosed by the investigator. Subjects with
additional diagnosis of Autism Spectrum Disorder or Anxiety Disorder will be allowed.
8. Subject has known or suspected human immune deficiency virus-positive status or has
diseases such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or
tuberculosis.
9. Subject is planning to commence psychotherapy or cognitive behavior therapy (CBT)
during the period of the study or had begun psychotherapy or CBT within 4 weeks
prior to Screening.
10. Subject is related to anyone employed by the sponsor, investigator, or study staff.
11. Subject has BMI less than 18 or greater than 36.
12. Subject has participated in another clinical trial within the 30 days preceding
Screening.
6.4
Subject Withdrawal 
All subjects have the right to withdraw from this study at any time. In addition, it is the right of 
the Investigator to remove subjects from the study as a result of adverse reactions, a protocol 
violation, or non-compliance, or any other reason.
Subjects must be discontinued for the 
following reasons:
x
Subject withdraws consent or requests discontinuation from the study for any reason;
x
Occurrence of a medical condition or circumstance that exposes the subject to substantial risk 
and/or does not allow the subject to adhere to the requirements of the protocol as determined 
by the Investigator;
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x
Any serious adverse event (SAE), clinical significant adverse event, severe laboratory 
abnormality, concomitant illness, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the subject;
x
Requirement for prohibited concomitant medication;
x
Termination of the study by the Sponsor or the regulatory authority.
Should a subject withdraw after administration of BPN14770 (or placebo), or should the 
Investigator decide to withdraw the subject, all efforts will be made to complete and report the 
protocol-stipulated observations up to the time of withdrawal. Week 12 procedures (see Section 
10.3.5 and Section 16.1 Schedule of Study Assessments) will be completed at the time of the 
subject’s withdrawal and an explanation provided as to why the subject is withdrawing or being 
withdrawn from the study.
In a case of subjects lost to follow-up, attempts to contact the subject must be made and 
documented in the subject’s medical records.
The Investigator must document the primary reason for discontinuation of a study subject on the 
appropriate case report form (CRF). If the reason for withdrawal is a clinical AE, monitoring 
will continue until the AE resolves or the Investigator assesses the AE as chronic and stabilized.
6.5
Replacement of Subjects
Subjects who do not meet eligibility criteria at Baseline will not be randomized and will be 
considered screen failures. Subjects who withdraw from the study for any reason will not be 
replaced.  
7
TREATMENT OF SUBJECTS
7.1
Treatment Arms
In this randomized double-blind, placebo-controlled, 2-period cross-over study, 30 patients will 
be randomized (1:1) to receive each of the following two treatments (one during each 12 week 
Treatment Period):
x
BPN14770 25 mg bid
x
Matching Placebo 
7.2
Study Medications
The 25 mg BPN14770 capsules and placebo capsules intended for use in this Phase 2 clinical 
trial are manufactured by Catalent, Inc. and will be packaged, labeled, and shipped for clinical 
use to sites by Sherpa Clinical Packaging.  
The 25 mg BPN14770 capsules are manufactured using a wet granulation process.  The
appropriate amount of granulation is blended with additional excipients to provide a
homogeneous blend.  The blend is then filled into hydroxypropyl methylcellulose (HPMC), size 
1, opaque white/opaque white capsules.  The capsules are packaged as 30 count in 60 cc, white, 
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high-density polyethylene (HDPE), round bottles with 33 mm, white polypropylene ribbed caps.  
The container-closure system is labeled with a study-specific label and should be stored at 
controlled room temperature (20ºC – 25ºC).  
7.3
Drug Accountability
The Investigator or designated study personnel is responsible for keeping accurate records of the 
study drugs (and other components) used in this study.
These records should include 
documentation of receipt, inventory, and disposition to subject.  The records should include
dates, quantities, batch/serial numbers, expiration dates (if applicable), and any unique code 
numbers assigned (if applicable).
The study monitor will review study drug records periodically during the conduct of the study.
At the end of the study, all partial and empty containers must be returned to the Sponsor or, if 
requested by the Sponsor, destroyed at the site according to standard operating procedure (SOP).
Records of destruction of study drug at the site must include bottle identifying information and 
number of capsules in each bottle. All documentation is to be filed in the Pharmacy Manual.  
In accordance with Good Pharmacy Practices, gloves should always be worn by study personnel 
when handling study drug.
7.4
Blinding
This is a randomized, double-blind study, meaning that neither site staff nor subject will know 
what the subject is receiving.
Randomization codes will be provided to the site pharmacy for use in case of an emergency code 
break requirement. Confirmation of receipt of the randomization code will be required by the 
Sponsor.
The site pharmacy will be responsible for maintaining the blind, consistent with 
protocol design, throughout the study, except in the case of an emergency code break.
The Investigator will be required to notify the Sponsor in the event of any breaking of the blind 
for any reason. Blinding is not to be broken during the study unless considered necessary by the 
Investigator for emergency situations for reasons of subject safety. The Investigator should 
contact the Medical Monitor before breaking the blind. When the blind is broken, the reason 
must be fully documented.
The subjects, Investigator, and all other study personnel involved with subject assessments will 
remain blinded to the actual treatment assignments of the subjects.
The Investigator will be 
ultimately responsible for ensuring that the integrity of the blind is maintained throughout the 
study.
7.5
Assignment of Subjects to Treatment Arms
A randomization schedule will be generated by a statistician unassociated with the study 
execution prior to the start of the study. Subjects will be randomized on Day 1and receive their 
first bottle of medication that same day. 
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7.6
Study Drug Administration
One capsule is to be taken orally in the morning, and one capsule is to be taken orally at night, 
with at least 120 mL (4 ounces) of liquid.  Doses should be taken at least 6 hours apart, and at 
least 30 minutes prior to or 1 hour after meals.
7.7
Prior and Concomitant Medications
A prior medication is defined as any psychotropic or anti-epileptic medication taken by the 
subject for more than 28 days during the 6 months prior to first dose of study drug (Day 1), 
which was subsequently discontinued within that same 6 month period.
A concomitant medication is defined as any medication taken 14 days prior to the first dose of 
study drug (Day 1) and during the study through the Week 13 Follow-up Visit should be 
recorded with indication, daily dose, and start and stop dates of administration.
Current treatment with no more than 3 prescribed psychotropic medications is allowed. Anti-
epileptic medications are permitted and are not counted as psychotropic medications if they are 
used for treatment of seizures. Anti-epileptics for other indications, such as the treatment of 
mood disorders, count towards the limit of three permitted medications. Permitted concomitant 
psychotropic medications must be at a stable dose and dosing regimen for at least 2 weeks prior 
to the commencement of study medication.
Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks prior to 
Screening and must remain stable during the period between Screening and the commencement 
of study medication.
7.8
Other Therapeutic Treatments
Behavioral and therapy treatments/interventions must be stable for 4 weeks prior to Screening 
and must remain stable during the period between Screening and the commencement of study 
medication, and throughout the study.
7.9
Dietary Guidelines
There are no dietary restrictions. Subjects should follow their usual eating behaviors.
7.10 Lifestyle Guidelines
There no lifestyle restrictions or guidelines associated with this study. 
8
STUDY PROCEDURES AND ASSESSMENTS
8.1
Informed Consent
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed.
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8.2
Medical /Surgical History 
Medical/Surgical history will be recorded at the Screening Visit as specified in Section 10.2.
Subject eligibility will be evaluated to determine all inclusion and none of the exclusion criteria 
are met. The Investigator will inquire with the subject on Period 1/Day 1 (Baseline, prior to 
randomization) to determine if there have been any changes in the subjects’s health affecting 
eligibility or requiring an update to their medical and surgical history.
8.3
Demographics and Social History
Demographics (sex, ethnicity, race) and social history (tobacco, alcohol, and/or drug use) will be 
recorded at the Screening Visit as specified in the Schedule of Assessments.
8.4
Stanford Binet Intelligence Scale
The Stanford Binet Intelligence Scale will be administered at Screening in order to support 
characterization of the study cohort and to determine whether cognitive and behavioral responses
are dependent on baseline level of cognitive functioning. The scale will be scored according to 
the Hessl z-deviation method to prevent floor effects.6 If the site has performed a Stanford-Binet 
assessment on a subject in the 6 months prior to screening, the result of that assessment may be 
used.
8.5
Physical Examination (Full and Abbreviated)
The full physical examination will be conducted at the Screening as specified in the Schedule of 
Assessments and will include:
x
General appearance
x
Skin
x
Eyes, ears, nose, and throat (EENT)
x
Head/neck
x
Extremities
x
Musculoskeletal examination
x
Respiratory examination
x
Cardiovascular assessment including rhythm and presence of cardiac abnormalities
x
Abdominal examination
x
Basic neurologic examination 
x
Any additional assessments necessary to establish baseline status or evaluate symptoms 
or adverse experiences
An abbreviated physical examination will be conducted at Period 1/Day 1 (if not the same day as 
Screening) and at Period 2/Week 12 visit and will include:
x
Any changes noted since the initial physical examination
x
General appearance
x
Skin
x
Extremities
x
Respiratory examination
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x
Cardiovascular assessment including rhythm and presence of cardiac abnormalities
x
Abdominal examination
Significant findings prior to the start of dosing will be recorded on the Medical History page of 
the CRF. Only changes from baseline physical examination findings that meet the definition of a 
treatment-emergent AE will be recorded as an AE.
8.6 Height, Weight, Body Mass Index
Body weight and height are to be measured at Screening.  Body weight will be repeated at the 
Period 1/Week12 and Period 2/Week 12 visits as specified in the Schedule of Assessments. 
Subjects will wear indoor clothing and remove their shoes prior to the measurements. Body 
Mass Index (BMI) will be calculated and recorded.
8.7 Vital Signs
Vital signs (pulse rate, blood pressure, respiration rate, and temperature) will be measured at 
Screening and during the Treatment Visits, as specified in the Schedule of Assessments.
Blood pressure and heart rate will be measured using a calibrated, fully automated machine with 
a cuff that is appropriate to the size of the upper arm. If a fully automated machine is not 
available, blood pressure may be measured manually. For each subject, measurement on the 
same arm (right or left) using the same method (either automated or manual) should occur 
throughout the study. All blood pressure measurements should be obtained with the subject in 
the sitting position, after the subject is at rest for 5 minutes.
Additional vital signs measurements may be performed as deemed medically necessary by the 
Investigator.
8.8 Electrocardiograms
Single 12-lead ECGs will be performed at every clinic visit except the Week 1 visit during each 
Period as specified in the Schedule of Assessments.
ECGs should be obtained after the subject has been resting comfortably in a supine position for 
approximately 5 minutes. ECGs will be collected prior to blood collection whenever possible.
ECGs will be assessed locally for eligibility determinations and safety. All ECG traces will be 
kept as source data.
For purposes of qualifying any given subject for study participation based on 
Inclusion/Exclusion Criteria, clinically significant out-of-range results may be repeated once.  
8.9 Laboratory Assessments
Appendix 16.2 Clinical Laboratory Analytes provides a list of the clinical laboratory tests that 
will be performed according to the collection schedule provided in the Schedule of Assessments.
Blood samples for chemistry and hematology and urine samples will be collected in accordance 
with acceptable laboratory procedures.
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Since a single-site study, an accredited local laboratory will be used to analyze the clinical 
laboratory samples.
8.10 Management of Abnormal Clinical Laboratory Tests
It is the Investigator’s responsibility to review the results of all lab tests as they become available 
and to document their review by signing and dating the lab report. For each lab test outside of 
the laboratory normal range, the Investigator must ascertain if this is a clinically significant 
change from baseline for the individual subject. This determination does not necessarily need to 
be made the first time an abnormal lab is observed. The Investigator may repeat the lab test or 
request additional tests to verify the results of the original lab test.
All clinically significant laboratory abnormalities occurring during the study that were not 
present at baseline should be followed and evaluated with additional tests if necessary until 
determination of the underlying cause or adverse event resolution.
8.11 Suicidality Assessment
Suicidality will be assessed at Screening and at Weeks 1, 2, 6, and 12 of each period. If a 
concern is detected, it is the responsibility of the Investigator to refer the subject for further 
evaluation and treatment.
A straightforward, caregiver-based assessment tool will be used, as more complex, subject-
completed instruments are not effective in this patient population. The caregiver will be asked 
three questions addressing whether the subject has wished for death or to go to sleep and not 
awaken, whether a suicide attempt has been made, and whether the subject has engaged in non-
suicidal, self-injurious behavior since the last visit.  If the answer to any of the three questions is 
“Yes,” the Investigator will further evaluate the suicidal risk of the subject.
8.12 Additional Safety Measures
Subjects and caregivers will be instructed to inform the study physician and/or research 
personnel of any AEs, including significant behavioral changes not within the typical variation 
for the subject, that occur at any time during the study.
Procedures will be completed as specified in this protocol unless contraindicated due to a 
reported AE.
If, in the judgement of the Investigator, additional testing is required to assess an adverse event 
or otherwise clinically significant event, this testing should be discussed first with the sponsor 
unless needed urgently.  
8.13 Exploratory Efficacy Assessments
8.13.1
Descriptions of Efficacy Assessment Instruments
Several assessment tools for cognitive and behavioral measures will be utilized in this 
exploratory study. Raw scores (not standardized) will be collected for all assessments, except for 
the Vineland -3 composite where age-equivalent scores will also be collected.
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8.13.1.1 NIH-TCB
The NIH-TCB, a component of the NIH Toolbox for Assessment of Neurological and Behavioral 
Function, was developed by a team of more than 300 scientists from nearly 100 academic 
institutions as part of the NIH Blueprint for Neuroscience Research to standardize evaluations in 
specific clinical populations for investigations of neurological development and change, disease 
recovery, and therapeutic interventions.7,8,9 The NIH-TCB is a battery of extensively validated 
computer-administered cognitive tests with utility across childhood and adolescence, early 
adulthood, and old age. The NIH-TCB assessments were designed to minimize floor and ceiling 
effects which often are present in testing batteries designed for the general population. 
Downward extensions of many of the NIH-TCB tests have been created to allow feasibility down 
to a mental age of 3. Therefore, there is good reason to believe that the assessments are 
appropriate for individuals with intellectual disabilities. In fact, a pilot study has been published 
showing good feasibility and test-retest reliability in FXS and Down syndrome, and the 
instructions and testing protocol has been adjusted (without changing construct validity) for 
individuals with intellectual disabilities based on issues identified in the pilot study.10 Further 
validation of the adjusted measure is ongoing.
The NIH-TCB includes 7 evaluations: Dimensional change card sort test (DCCS, measure of 
cognitive flexibility), Flanker inhibitory control and attention test (measure of inhibition and 
visual attention), Picture sequence memory test (measures episodic memory), List sorting 
working memory test (measures immediate recall and sequencing of different visually and orally 
presented stimuli), Pattern comparison test (measures processing speed), Oral reading 
recognition test (measures recognition of letters and words), Picture vocabulary test (measures 
receptive vocabulary).
8.13.1.2 Test of Attentional Performance (KiTAP)
The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests 
measuring different basal as well as higher-order components of attention and executive 
functioning.11 Each subtest can be assessed separately. Four subtests will be utilized in this 
study: alertness, distractibility, go-nogo, and flexibility. To ensure optimal motivation and 
compliance, all subtests are designed in the form of short games with an enchanted castle 
theme. The four subtests chosen for use in this study have been utilized in FXS populations and 
shown to be feasible, reproducible with evidence of clinical validity when scores are compared 
with standardized behavioral questionnaires addressing relevant functions. The KiTAP has 
shown evidence of response to pharmacological intervention in clinical trials of AFQ056 and 
metadoxine in FXS.12,13
8.13.1.3 Clinical Global Impression
The CGI-I (and CGI-S) are gold standard global measures of severity and change with treatment 
in placebo-controlled pharmacotherapy trials in developmental disabilities and have been used 
extensively in prior clinical trials in FXS. 14,15
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8.13.1.3.1 Clinical Global Impression Severity: Investigator Rated (CGI-S)
7KH &OLQLFDO *OREDO ,PSUHVVLRQí6HYHULW\ &*,-S) is a global measure to provide a clinical 
judgment of a subject’s overall condition based on a trained clinician’s assessment of cognition, 
behavior and activities of daily living.16 The assessment of severity will be made with a 7-point 
scale: 1, not ill; 2, very mild;  3, mild; 4, moderate; 5, marked; 6, severe; 7, extremely severe. 
The comparison will be made with respect to the overall experience of the clinician with 
individuals of the same age and sex. 
8.13.1.3.2 Clinical Global Impression Improvement: Investigator –Rated (CGI-I)
The Clinical Global Impression – Improvement (CGI-I) assessment is a 7-point scale that 
requires the clinician to assess how much the subject's illness has improved or worsened relative 
to a baseline state at the beginning of the intervention, and rated as: 1, very much improved; 2, 
much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, 
very much worse. 16
Completion of this scale requires the clinician to rate how much the subject’s illness (including 
behavioral and adaptive functioning) has improved or worsened relative to a baseline state. The 
CGI-I must be administered by the same rater for a given subject at all applicable visits 
throughout the trial. 
8.13.1.4
VAS Rating Scale
In an attempt to measure the level of behavioral difficulty experienced by the parent/caregiver 
with respect to the child with FXS, the VAS will allow parents to mark on a visual line 
measuring 10 cm with one side marked “worst behavior” and the other side marked “best 
behavior.” The caregiver will rate the subject’s behavior with respect to three domains: daily 
functioning, anxiety/irritability and language; with guidance form the investigator, the caregiver 
will select a behavior within each domain that will be assessed throughout the study. The 
caregiver marks are measured in milliimeter distance so that improvements or worsening of 
behavior over the treatment period can be evaluated. The VAS has been successfully used in 
multiple clinical trials conducted in the FXS population.17 The caregiver completing the 
assessment should remain the same at all applicable visits throughout the trial.
8.13.1.5 Aberrant Behavior Checklist (ABC)
The Aberrant Behavior Checklist- Community Edition (ABC) is a 58-item parent/caregiver 
rating scale used to assess behaviors across five dimensions or subscales: irritability, 
hyperactivity, lethargy/withdrawal, stereotypy, and inappropriate speech.18 Items are evaluated 
on a four-point Likert scale ranging from 0 (not at all a problem) to 3 (the problem is severe in 
degree).  This scale has been used extensively in FXS in clinical trials and other projects. The 
ABC will be scored using the FXS-specific factoring system (ABC-FX). The caregiver 
completing the assessment should remain the same at all applicable visits throughout the trial.
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8.13.1.6 Anxiety Depression and Mood Scale (ADAMS)
The ADAMS (Anxiety, Depression, and Mood Scale) is a 28-item behavior-based informant 
instrument rated by the parent/caregiver and designed to assess anxiety, depression and mood 
disorders in individuals with intellectual disability.19 Items are rated on a scale of 0 (“behavior 
has not occurred, or is not a problem”) to 3 (“behavior occurs a lot, or is a severe problem”). The 
scale is composed of 5 factors which address: Manic/Hyperactive Behavior, Depressed Mood, 
Social Avoidance, General Anxiety and Obsessive/Compulsive Behavior. A caregiver identified 
upon enrollment of subject should have intimate knowledge of the subject’s situation and level of 
impairment to be able to provide accurate information as required to complete the ADAMS. The 
caregiver completing the assessment should remain the same at all applicable visits throughout 
the trial.
8.13.1.7 Vineland-3 Rating Scale
The Vineland Adaptive Behavior Scales, Third Edition (Vineland-3)20 assesses adaptive 
behavior in five domains, each with subdomains. The following three domains will be assessed 
in this study, as most applicable to the FXS population:
1. Communication
o
Subdomains: Receptive, Expressive, Written
2. Daily Living Skills
o
Subdomains: Personal, Domestic, Community
3. Socialization
o
Subdomains: Interpersonal Relationships, Play and Leisure, Coping Skills
The Vineland-3 will be administered as a standardized interview to a parent/caregiver by trained 
study staff trained and authorized to perform the interview. The Vineland-3 must be administered 
by the same rater for a given subject at all applicable visits throughout the trial. The caregiver 
completing the assessment with the study staff member should also remain the same at all 
applicable visits throughout the trial. If the site has performed a Vineland-3 assessment on the 
subject in the 6 months prior to screening, the results of that assessment may be used for the 
baseline (Day 1) assessment in this study.
8.13.1.8 Event-Related Potentials (ERP)
Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific 
sensory, cognitive, or motor events from an overall EEG. 21,22Auditory stimuli are presented and 
EEG events assessed in relation to timing of the stimuli. For this study, an ERP protocol 
developed to measure auditory habituation to trains of repeated stimuli, resting state delta power, 
and CHIRP responses in FXS will be used.23 This protocol has shown feasibility and clinical 
validity based on comparison to sensory hypersensitivity on the Sensory Profile in FXS. The 
EEGs will be read by 
 who developed the protocol and has extensive 
experience in ERP evaluation.
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8.13.1.9 Eye Tracking
Eye tracking has been successfully used to assess social gaze in FXS.24 Testing will be
conducted in a quiet room with the lights turned off. The eye tracker (Tobii) will be calibrated 
for each subject at the beginning of each session. Following calibration, subjects will view 
pictures shown on the screen. Each assessment begins with presentation of a scrambled face 
image for 1 s followed immediately by its matched face image for 3 s. An inter-trial interval 
(ITI) containing a uniform grey screen is shown for 0.5, 1, or 2 s, randomly determined. The 
order of face presentation is pseudorandomized and each eye tracking session lasts
approximately 6 min. Measurements include looking time to the eye region of interest (ROI), and 
number of fixations to the eye ROI, as well as pupil dilatation by pupilometry. These 
measurements have been shown to have good test-retest reproducibility. All measurements are 
analyzed offline by a trained specialist.
8.13.2
Timing of Efficacy Assessments
8.13.2.1 Baseline (Period 1/Day 1)
The following exploratory efficacy assessments will be performed at Baseline (Period 1/ Day 1, 
prior to randomization):
x
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
x
Test of Attentional Performance (KiTAP)
x
Clinical Global Impression Severity – Investigator rated (CGI-S)
x
VAS Rating Scale using patient-specific behavioral anchors
x
Aberrant Behavior Checklist (ABC) 
x
Anxiety, Depression, and Mood Scale (ADAMS)
x
Vineland-3 Rating Scale
x
Event-Related Potentials (ERP) 
x
Eye Tracking
8.13.2.2 Week 6 (Periods 1 and 2)
The following cognitive tests will be assessed at Week 6 during each Period:
x
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
x
Test of Attentional Performance (KiTAP)
x
Clinical Global Impression Severity – Investigator rated (CGI-S)
x
Clinical Global Impression Improvement – Investigator rated (CGI-I)
x
Visual Analog Scale (VAS) assessment of patient-specific behavioral anchors)
8.13.2.3 Week 12 (Periods 1 and 2)
The full battery of cognitive tests will be performed at Week 12 during each Period:
x
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
x
Test of Attentional Performance (KiTAP)
x
Clinical Global Impression Severity – Investigator rated (CGI-S)
BPN14770 
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x
Clinical Global Impression Improvement – Investigator rated (CGI-I)
x
Visual Analog Scale (VAS) assessment of patient-specific behavioral anchors
x
Aberrant Behavior Checklist (ABC) 
x
Anxiety, Depression, and Mood Scale (ADAMS)
x
Event-Related Potentials (ERP)
x
Eye Tracking 
x
Vineland-3 Rating Scale
8.14 Pharmacokinetic Assessment
8.14.1
Plasma Pharmacokinetic Samples
Blood samples for BPN14770 concentrations will be drawn at screening and during the clinic 
visit at Week12 during each Period. Samples will be drawn at the time of the clinic visit, with 
documentation of time of day testing was performed, and time of day of most recent dose of 
study medication.  
Pharmacokinetic samples will be retained and may also be utilized subsequently for biomarker 
assessment.  Blood samples (1 u 4 mL) will be collected in Vacutainer tubes containing 
K2-EDTA as a preservative.
8.14.2
Processing and Shipment of Pharmacokinetic Samples
Blood samples will be kept on wet ice from the time of collection and throughout processing 
until frozen.
Blood samples will be centrifuged at 1500 x g (gravity) for 10 minutes at 4°C. The resulting 
plasma samples will be harvested and transferred into appropriately labeled polypropylene 
screw-cap tubes.
Pharmacokinetic samples will be placed in a freezer at -80°C within 60 
minutes of the blood draw.
Samples will remain frozen until assayed.
A more detailed 
description of plasma sample preparation requirements may be provided by the analytical 
laboratory and will supersede those provided in this protocol. Appropriate documentation will 
be placed in the study master file at the Clinical Site.
The samples will be transferred to the analytical laboratory after completion of the study or at 
mutually agreed upon time points during the clinical conduct of the study. Prior to shipment, the 
samples will be appropriately packed in a Styrofoam cooler containing dry ice. Sufficient dry ice 
will be added to ensure that the samples will remain frozen for at least 72 hours for remote 
shipments.
The shipment will be accompanied by documentation containing the following 
information: name of the study drug product, protocol number, number of subjects, and number 
of samples included in the shipment.
All frozen pharmacokinetic samples will be transferred with accompanying documentation to:
Senior Research Analyst/Investigator
CMIC, Inc.
2860 Forbs Avenue
Hoffman Estates, IL 60192-3702
Telephone: 847.945.0407
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Protocol:  BPN14770-CNS-203
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Pharmacokinetic samples at CMIC, Inc. will be stored in a freezer at -80°C.
8.14.3
Analytical Method
Plasma samples will be analyzed for BPN14770 using a validated assay.25
Samples will only be analyzed for subjects whose treatment included administration of 
BPN14770.  Samples will not be analyzed when matching placebo for BPN14770 was 
administered.
8.14.4
Plasma Pharmacokinetic Parameters
BPN14770 plasma levels will be presented in tabular form by Period at Week 12, and a listing of 
all subjects’ data will be provided.
8.15 Biomarker Assessments
Biomarker samples will be collected concurrently with the pharmacokinetic samples at screening 
and at the Week 12 visits at the end of each Period.  Samples will be processed in the same 
manner as the pharmacokinetic samples (see Section 8.14.2). Biomarker samples will be shipped 
to the sponsor for analysis.
9
EVALUATION AND REPORTING OF ADVERSE EVENTS 
9.1
Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. All adverse events, including observed or volunteered 
problems, complaints, or symptoms, are to be recorded on the appropriate CRF.
Adverse events, which include abnormal and clinically significant clinical laboratory test 
variables, will be monitored and documented from the time of first dose until study participation 
is complete (the Follow-up Visit). Subjects should be instructed to report any adverse event that 
they experience to the Investigator. Any medical condition already present prior to the subject 
taking the first dose of study treatment will be reported in the medical history. Should any 
changes in the subject’s health occur between consent and first dose of study treatment, , the 
Investigator will make corresponding updates to medical history.
Beginning with the first dose of study drug, the Investigator will make an assessment for adverse 
events at each visit and record all adverse events, non-serious and serious, on the appropriate 
adverse event CRF. Any pre-existing medical condition or signs or symptoms that change 
adversely in severity, frequency, or seriousness (outside of the range of typical variation of the 
symptom over time in the past for the patient) after the subject takes the first dose of study drug 
and through the Follow-up Visit should be reported as an adverse event.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the CRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the CRF. 
Additionally, the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure. 
Concomitant procedures should be recorded as such on the appropriate CRF. 
Clinically significant abnormal laboratory values or other examinations (e.g., ECG) that are 
detected after the first dose of study drug and worsen during the study should be reported as 
adverse events. An abnormal laboratory result that is not verified by repeat testing does not 
necessitate reporting as an adverse event. The Investigator will exercise his or her medical, 
scientific, and clinical judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, 
or are no longer clinically significant. Any abnormal test that is determined to be an error does 
not require reporting as an adverse event.
Treatment of any adverse reactions will be evaluated and managed by a physician.
9.2
Definitions
9.2.1
Adverse Drug Reaction
For adverse events with a causal relationship to study drug, follow-up by the Investigator will be 
required until the event or its sequelae resolve or stabilize to a level acceptable to the 
Investigator.
9.2.2
Unexpected Adverse Event/ Unexpected Adverse Drug Reaction
An unexpected AE/unexpected suspected adverse reaction is an AE or suspected adverse 
reaction that is not listed in the Investigator Brochure or is not listed at the specificity or severity 
that has been observed; or, if an Investigator Brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or elsewhere in 
the current application, as amended.
9.2.3
Serious Adverse Events
An adverse event or adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:
x
Death;
x
A life-threatening adverse event;
x
NOTE: An adverse event or adverse reaction is considered “life-threatening” if, in view 
of either the Investigator or Sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an event that, had it occurred in a more severe form, might 
have caused death.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Date: 25 June 2018
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x
Requires hospitalization or prolongation of existing hospitalizations;
NOTE: Any hospital admission with at least one overnight stay will be considered an 
inpatient hospitalization. An emergency room visit without hospital admission will not be 
recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent. However, unexpected complications 
and/or prolongation of hospitalization that occur during elective surgery should be 
recorded as adverse events and assessed for seriousness. Admission to the hospital for 
social or situational reasons (i.e., no place to stay, live too far away to come for hospital 
visits) will not be considered inpatient hospitalizations. 
x
A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions;
x
A congenital anomaly/birth defect; or
x
An important medical event.
NOTE: Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and 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 hospitalizations, or the development of drug dependency or drug abuse.
9.3
Assessment of Adverse Events by the Investigator
9.3.1
Causality/Relatedness
The relationship of an adverse event to the administration of the study drug is to be assessed by 
the Investigator according to the following definitions:
Not Related (unlikely related, unrelated, not related, no relation) – The time course between the 
administration of study drug and the occurrence or worsening of the adverse event rules out a 
causal relationship and/or another cause (e.g., medical history, concomitant drugs, therapies, and 
complications) is suspected.
Related (possibly related, related) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event is consistent with a causal relationship and 
no other cause (e.g., medical history, concomitant drugs, therapies, and complications) can be 
identified.
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. The following factors should also be considered:
•
The temporal sequence from study drug administration - The event should occur after
the study drug is given. The length of time from study drug exposure to event should
be evaluated in the clinical context of the event.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
______________________________________
Confidential 


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Date: 25 June 2018
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•
Underlying, concomitant diseases (medical history) -
Each report should be
evaluated in the context of the natural history and course of the disease being treated
and any other disease the subject may have.
•
Concomitant drug - The other drugs the subject is taking or the treatment the subject
receives should be examined to determine whether any of them might be recognized
to cause the event in question.
•
Known response pattern for this class of study drug - Clinical and/or preclinical data
may indicate whether a particular response is likely to be a class effect.
•
Exposure to physical and/or mental stresses - The exposure to stress might induce
adverse changes in the recipient and provide a logical and better explanation for the
event.
•
The pharmacology and PK of the study drug - The known pharmacologic properties
(absorption, distribution, metabolism, and excretion) of the study drug should be
considered.
9.3.2
Severity
The Investigator is responsible for assessing the severity (intensity) of each adverse event as 
mild, moderate, or severe according to the following definitions:
Mild – An event that is easily tolerated and generally not interfering with normal daily activities.
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities.
Severe – An event that is incapacitating with inability to work or perform normal daily activities.
It should be noted that a severe AE need not be serious and that a serious adverse event (SAE) 
need not, by definition, be severe.
9.3.3
Adverse Event Monitoring and Follow-up
Subjects who experience AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the Investigator. In accordance with good medical practice, all 
AEs must be followed to satisfactory resolution or stabilization of the event(s), or, if a chronic 
condition, until fully characterized. All follow-up results are to be reported to the Sponsor. Any 
actions taken and follow-up results must be recorded either on the appropriate page of the CRF 
or in a follow-up letter to the Sponsor, as well as in the subject’s source documentation. Follow-
up laboratory results should be filed with the subject’s source documentation.
For all AEs that require the subject to be discontinued from the study, relevant clinical 
assessments and laboratory tests must be repeated at appropriate intervals until final resolution or 
stabilization of the event(s).
Subjects who have an ongoing SAE at study completion or study withdrawal must be followed 
until the event resolves or the event or sequela stabilizes. Subjects who have non-serious AEs 
that are ongoing at study completion or study withdrawal and are considered at least possibly 
BPN14770 
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related to study treatment must be followed until resolution or for 30 days after the last dose of 
study drug, whichever comes first.
9.3.4
Reporting Serious Adverse Events
From the time of informed consent until 30 days following the last administration of study drug 
the Investigator or designee will notify the sponsor contact within 24 hours after the SAE 
detection, observation, or report of occurrence (regardless of the relationship to study treatment).
The Sponsor contact information for SAE reporting is provided below:
Tetra Discovery Partners, Inc.
Email: 
Office: 
24-hour contact number (Cell): 
and
 
Consulting for Tetra Discovery Partners, Inc.
Email: 
Office: 
 
24-hour contact number (Cell): 
The SAE report must contain the following information:
Study name/number (for EU also the EudraCT number)
Study drug
Investigator details (name, phone, fax, e-mail)
Subject number (randomization number)
Subject initials
Subject demographics  (age, date of birth, sex, weight)
Clinical event
o Description
o Date of onset
o Treatment (drug, dose, dosage form)
o AE relationship to study drug
o Action taken regarding study drug in direct relationship to the AE
If the AE was fatal or life-threatening
Cause of death (whether or not the death was related to study drug)
Autopsy findings (if available)
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. Within 24 hours of receipt of follow-up information, the Investigator must update 
the Sponsor and submit any supporting documentation (e.g., subject discharge summary or 
autopsy reports).
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
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Date: 25 June 2018
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Any new SAE that occurs within one month after the study period and is considered to be 
possibly related to the investigational product should be recorded and reported immediately to 
the Sponsor.
All serious event reporting will adhere to Code of Federal Regulations (CFR), specifically 21 CFR 
312.32 (7- and 15-day alerts) for Investigational New Drugs (IND). The clinical research site 
will be responsible for reporting SAEs to the Institutional Review Board (IRB) per FDA 
regulations. The Sponsor will be responsible for reporting and processing any SAEs to the FDA 
or other applicable regulatory agency.
10 STUDY PROCEDURES AND ASSESSMENTS BY VISIT
10.1 Schedule of Assessments
The study timetable in Section 16.1 shows the schedule of planned study procedures.
Every 
effort should be made to adhere to this procedure schedule.
10.2 Screening (Day -28 to Day -1)
The study will consist of a Screening period of 28 days or less. Screening and Baseline visits 
may be combined.
Each potential study participant will have the following assessments completed by the 
Investigator or designee up to 28 days prior to the first dose of study medication:
x
Obtain informed consent;
x
Obtain medical/surgical history;
x
Obtain demographics and social history (tobacco, alcohol, and/or drug use);
x
Obtain prior/concomitant medication use;
x
Conduct full physical exam;
x
Obtain height and weight;
x
Obtain vital signs;
x
Conduct single ECG;
x
Draw fasting blood samples for Chemistry and Hematology and for PK and biomarkers
(following a minimum 8-hour fast);
x
Collect urine for safety urinalysis;
x
Assess suicidality;
x
Complete Stanford-Binet assessment;
o
If the site has performed a Stanford-Binet test on the subject in the previous 6
months, the results of that assessment may be used for Screening in this study.
x
Evaluate inclusion and exclusion criteria.
10.3 Baseline (Period 1/Day 1)
Subjects will return to the clinic for the Period 1/Day 1 Visit (Baseline) following successful 
screening. If clinic processes allow, the Screening and Baseline visits may be combined; in this 
case, it is not necessary to repeat vital signs nor to conduct the abbreviated physical exam.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Date: 25 June 2018
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10.3.1
Prior to Randomization
The following assessments will be completed:
x
Conduct abbreviated physical exam (not to be repeated if the Screening and Baseline 
visits occur on the same day);
x
Obtain vital signs (not to be repeated if the Screening and Baseline visits occur on the 
same day);
x
Record any updates to medical/surgical history;
x
Record any updates to prior/concomitant medication use;
x
Re-evaluate inclusion and exclusion criteria based on preceding activities; 
x
Verify continued eligibility;
x
Complete baseline cognitive assessments:
o
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
o
Test of Attentional Performance (KiTAP)
o
Clinical Global Impression Severity – Investigator rated (CGI-S)
o
Visual Analog Scale (VAS) assessment of patient-specific behavioral anchors
o
Aberrant Behavior Checklist (ABC)
o
Anxiety, Depression, and Mood Scale (ADAMS)
o
Vineland-3 Rating Scale

If the site has performed a Vineland-3 assessment on the subject in the 6
months prior to screening, the results of that assessment may be used for
baseline (Day  1) in this study.
o
Event-Related Potentials (ERP)
o
Eye Tracking
If subject remains eligible for the study:
x
Randomize subject;
x
Dispense study medication.
10.3.2
Week 1 (Periods 1 and 2)
The following assessments will be completed at the Week 1 Visit during each Period:
x
Telephone call to:
o
Assess suicidality;
o
Record any updates to concomitant medication use , and
o
Assess and record any adverse events.
10.3.3
Week 2 (Periods 1 and 2)
The following assessments will be completed at the Week 2 Visit during each Period:
x
Collect vital signs;
x
Conduct ECG (single);
x
Draw fasting blood samples for Chemistry and Hematology (following a minimum 8-
hour fast);
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Protocol:  BPN14770-CNS-203
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Date: 25 June 2018
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x
Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance;
x
Assess suicidality;
x
Record any updates to concomitant medication use; and
x
Assess and record any adverse events.
10.3.4
Week 6 (Periods 1 and 2)
The following assessments will be completed at the Week 4 Visit during Periods 1 and 2:
x
Collect vital signs;
x
Assess suicidality;
x
Conduct the following cognitive tests:
o
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
o
Test of Attentional Performance (KiTAP)
o
Clinical Global Impression Severity – Investigator rated (CGI-S)
o
Clinical Global Impression Improvement – Investigator rated (CGI-I)
o
Visual Analog Scale (VAS) assessment of patient-specific behavioral anchors
x
Collect study medication and record  pill count remaining in bottle to assess dosing
compliance;
x
Dispense study medication;
x
Record any updates to concomitant medication use; and
x
Assess and record any adverse events.
10.3.5
Week 12 (Periods 1 and 2)
The following assessments will be completed at the Week 12 Visit during Periods 1 and 2:
x
Collect weight;
x
Collect vital signs;
x
Conduct ECG (single);
x
Draw fasting blood samples for Chemistry and Hematology (following a minimum 8-
hour fast);
x
Collect urine for safety urinalysis;
x
Assess suicidality;
x
Draw blood sample for pharmacokinetic analyses;
x
Conduct the following cognitive tests:
o
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
o
Test of Attentional Performance (KiTAP)
o
Clinical Global Impression Severity – Investigator rated (CGI-S)
o
Clinical Global Impression Improvement – Investigator rated (CGI-I)
o
Visual Analog Scale (VAS) assessment of patient-specific behavioral anchors
o
Aberrant Behavior Checklist (ABC)
o
Anxiety, Depression, and Mood Scale (ADAMS)
o
Vineland-3 Rating Scale
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
______________________________________
Confidential 


Protocol:  BPN14770-CNS-203
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Date: 25 June 2018
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o
Event-Related Potentials (ERP)
o
Eye Tracking
x
Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance;
x
Record any updates to concomitant medication use; and
x
Assess and record any adverse events.
Period 1/Week 12 and Period 2 /Day 1 activities are conducted at the same clinic visit.  It is not 
necessary to repeat assessments of vital signs and ECG.
10.3.6
Week 13 (Period 2, Final Contact at End of Study)
x
Telephone call to:
o
Record any updates to concomitant medication use ,
o
Assess and record any adverse events, and
o
Record final subject disposition.
10.3.7
Early Termination
It is hoped that all subjects can be followed through to the conclusion of the study at Period 
2/Week 13.  However, if an early termination occurs, the Week 12 procedures should be 
completed at the time of the subject’s withdrawal (if possible) and an explanation provided as to 
why the subject is withdrawing or being withdrawn from the study. Procedures to be completed 
early termination:
x
Collect weight;
x
Collect vital signs;
x
Conduct ECG (single);
x
Draw fasting blood samples for Chemistry and Hematology (following a minimum 8-
hour fast);
x
Collect urine for safety urinalysis;
x
Assess suicidality;
x
Draw blood sample for pharmacokinetic analyses;
x
Conduct the following cognitive tests:
o
NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB)
o
Test of Attentional Performance (KiTAP)
o
Clinical Global Impression Severity – Investigator rated (CGI-S)
o
Clinical Global Impression Improvement – Investigator rated (CGI-I)
o
Visual Analog Scale (VAS) assessment of patient-specific behavioral anchors
o
Aberrant Behavior Checklist (ABC)
o
Anxiety, Depression, and Mood Scale (ADAMS)
o
Vineland-3 Rating Scale
o
Event-Related Potentials (ERP)
o
Eye Tracking
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Confidential 


Protocol:  BPN14770-CNS-203
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Date: 25 June 2018
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x
Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance;
x
Record any updates to concomitant medication use;
x
Assess and record and adverse events; and
x
Record final subject disposition.
11 PLANNED STATISTICAL METHODS
11.1 Sample Size
Given the exploratory nature of this study, a definitive sample size calculation is not possible. 
However, for the sake of providing an evaluation of the potential power to detect a meaningful 
difference between treatments, a crossover study having no carryover effects with 80% power, a 
5% alpha level, and a common standard deviation of 3 units, a sample size of 30 evaluable 
patients (15 per sequence group) will allow detection of an effect size of approximately 2.25 
units on the ABC Total Score outcome measure. If carryover effects or excessive dropouts allow 
only for a first Period analysis, a sample size of 15 per group during the first period would allow 
for detection of an effect size of 3.19 units.
11.2 Demographics
Summary statistics [number (n), mean, standard deviation (SD), minimum, median, and 
maximum] will be tabulated for the observed values for all continuous demographic parameters.
Frequencies and percentages will be tabulated for categorical data.
11.3 Analysis Populations
The primary efficacy population will be the intent to treat (ITT) efficacy population, which will 
include all randomized subjects who received at least one dose of treatment and returned for at 
least one follow-up visit. The completers population (CP), defined as all randomized subjects 
who completed  both  treatment periods with no significant protocol violations, will be used to 
evaluate the robustness of the ITT results.
The Safety population will include all randomized subjects who received at least one dose of 
study treatment.
11.4 Efficacy: Cognitive Testing Analysis
All cognitive parameters will be summarized at each time point collected and standard 
descriptive statistics provided. Baseline measurements are defined as those obtained on Day 
1/Period 1 prior to receipt of any study medication.  For cognitive parameters measured at 
baseline, change from baseline will also be calculated and standard descriptive statistics provided 
for each time point. Linear mixed models will be used to explore potential treatment effects.
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11.5 Safety Analysis
Safety analysis will be based on all subjects receiving at least one dose of study medication.
Treatment emergent AEs will be summarized based on the frequency of AEs and their severity 
for all dosed subjects.  Adverse Events (AEs), including clinically meaningful laboratory 
abnormalities and significant behavioral changes, will collected. AE severity and relatedness to 
treatment will be assessed. AEs will be tabulated for placebo and BPN14770 treatments using 
preferred terms and system organ classes. Summaries will also be provided by severity and 
relationship to treatment. Serious Adverse Events (SAEs) will be summarized separately, in a 
manner similar to that used for Adverse Events.
Overall safety and tolerability will be assessed by clinical and/or statistical review of all safety 
parameters including adverse experiences, laboratory values, vital signs, physical exams, and 
ECG data.  General clinical and laboratory adverse events will be presented in frequency tables. 
Summary statistics (n, mean, SD, median, and range (minimum, maximum) will be tabulated for 
the observed values and the change (or percent change) from baseline for all continuous 
parameters for vital signs, ECG, and laboratory tests.
11.6 Pharmacokinetic Analysis
BPN14770 plasma levels will be presented in listing form by Period, Treatment and subject.
11.7 Biomarker Analysis
Biomarker analysis will be exploratory and will follow reporting of the clinical study, as the 
biomarker analyses to be conducted may be partially determined by clinical results observed in 
the study.
12 DATA MANAGEMENT
12.1 Data Handling
Data will be recorded at the site on CRFs and reviewed by the CRA during monitoring visits. 
The CRA will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC 
system. A CRF will be considered complete when all missing, incorrect, and/or inconsistent data 
has been accounted for.
12.2 Computer Systems
Data will be collected and processed using a validated EDC system. The system and procedures 
are designed in compliance with Title 21 of the Code of Federal Regulations (21 CFR Part 11).
12.3 Data Entry
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or 
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correct study data. These procedures must comply with 21 CFR Part 11 and other appropriate 
international regulations. All passwords will be strictly confidential.
The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered on the CRFs and any other data 
collection forms.  
12.4 Data Validation
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries.
The CRFs must be reviewed and signed by the Investigator.
13 INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL
13.1 Ethical Conduct of the Study
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
that are described in the protocol and to conduct the study in accordance with the CFRs (21 CFR 
§ 11, 50, 54, 56, and 312 Subpart D), which originate from the ethical principles laid down in the
current revision of the Declaration of Helsinki, Good Clinical Practice (GCP), and the policies
and procedures as outlined by the ethical requirements for IRB review and informed consent
form.
The Investigator agrees to allow monitoring and auditing of all essential clinical study 
documents by the Sponsor or its authorized representatives and inspection by the FDA or other 
appropriate regulatory authorities.  Monitoring and auditing visits by the Sponsor will be 
scheduled with the appropriate staff at mutually agreeable times periodically throughout the 
study.
The Investigator will ensure proper implementation and conduct of the trial, including those 
study-related duties that are delegated to other appropriately qualified individuals.  The 
Investigator will ensure that study staff cooperates with monitoring and audits and will 
demonstrate due diligence in recruiting and screening study subjects.
For this study and all studies conducted under an IND, the Investigator must sign and return a 
completed Form FDA 1572, “Statement of Investigator,” to the Sponsor.
13.2 Institutional Review Board (IRB)
Before initiation of the study, the Investigator must obtain approval or favorable opinion of the 
research protocol, informed consent form, and any advertisement for subject recruitment from an 
IRB complying with the provisions specified in 21 CFR §56 and applicable pertinent state and 
federal requirements of each participating location including International Conference on 
Harmonization (ICH) and GCP guidelines.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Institutional review boards must be constituted according to the applicable laws.
It is the 
responsibility of each investigational site to submit the protocol, Investigators’ Brochure, subject 
informed consent, subject recruitment materials (if applicable), and other documentation as 
required by the IRB to their IRB for review and approval. A copy of the written approval must 
be provided to the Sponsor.
Sites must adhere to all requirements stipulated by their respective IRB.
This includes 
notification to the IRB regarding: protocol amendments, updates to the subject informed consent, 
recruitment materials intended for viewing by subjects, IND Safety Reports, serious and 
unexpected AEs, reports and updates regarding the ongoing review of the trial at intervals 
specified by the respective IRB, and submission of final summaries to IRB.
The Investigator must promptly inform his/her IRB of all unexpected SAEs considered possibly 
related to the treatment or other critical safety information reported by the clinical site.
13.3 Informed Consent
The informed consent form (ICF) and any changes to the ICF made during the course of the 
study must be agreed to by the Sponsor or designee and the IRB prior to its use and must be in 
compliance with all ICH GCP, provisions specified in 21 CFR §50, and applicable pertinent state 
and federal requirements.
The Investigator, or a person delegated the responsibility by the Investigator, must ensure that 
each study subject (or legally acceptable representative) is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator or delegate will allow the 
subject adequate opportunity to read the written informed consent and ask any questions. The 
Investigator will obtain written informed consent from each subject before any study-specific 
activity is performed and should document in the source documentation that consent was 
obtained prior to any study-specific activity. The original signed copy of the ICF must be 
maintained by the Investigator and is subject to inspection by a representative of the Sponsor, 
their representatives, auditors, the IRB/EC and/or regulatory agencies. A copy of the signed ICF 
will be given to the subject.
13.4 Study Monitoring
The role of the study monitor is to verify the rights and well-being of the subjects are protected, 
the data is accurate, complete, and verifiable from source documents, and the conduct of the 
study is in compliance with the protocol, Declaration of Helsinki, ICH GCP, and applicable 
regulatory requirements.
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, 
the Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: Clinical Protocol, Investigator’s 
Brochure, CRFs and procedures for their completion, informed consent process, management of 
investigational product, and the procedure for reporting adverse events such as SAEs.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Date: 25 June 2018
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The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. 
During the monitoring visits, information recorded on the CRFs will be verified against source 
documents and requests for clarification or correction may be made. After the CRF data is 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to 
help monitor the clinical study. If necessary, requests for clarification or correction will be sent 
to investigators. The Investigator and his/her staff will be expected to cooperate with the monitor 
and provide any missing information, whenever possible.
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log 
and findings documented in a follow-up letter.
It is important that the Investigator and their relevant personnel are available during the 
monitoring visits and that sufficient time is devoted to the process.
13.5 Disclosure of Information
It is understood by the Investigator that the information and data included in this protocol is 
confidential and proprietary to the Sponsor, Tetra Discovery Partners, Inc. This information may 
be disclosed to study personnel under the Investigator’s supervision and the Institutional Review 
Board for the purpose of evaluating or conducting the study under the condition that they 
maintain confidentiality.  The contents of this document may not be used in any other clinical 
trial, disclosed to any other person or entity, and/or published without the prior written 
permission of the Sponsor.  The foregoing shall not apply to disclosure required by any 
regulations; however, the Investigator will give prompt notice to the Sponsor of any such 
disclosure.
The medical information and completed original CRFs are the sole property of the Sponsor and 
should not be made available in any form to third parties, except for authorized representatives of 
the Sponsor or appropriate regulatory authorities, without written permission from the Sponsor.
Information for a specific subject may be provided to the subject, caregiver, and/or guardian if 
deemed by the investigator to be helpful in the clinical management of the subject.
13.6 Record Storage and Retention
Records of subjects, source documents, monitoring visit logs, CRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 
are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records.
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To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to 
link records, e.g., CRFs and hospital records), all original signed ICFs, copies of all CRFs, SAE 
forms, source documents, and detailed records of treatment disposition. The records should be 
retained by the Investigator according to specifications in the ICH guidelines, local regulations, 
or as specified in the Clinical Study Agreement, whichever is longer. The Investigator must 
obtain written permission from the Sponsor before disposing of any records, even if 
retention requirements have been met.
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to the Sponsor.
13.7 Protocol Amendments and Deviations
Any amendments to the study protocol will be communicated to the Investigator by the Sponsor
or authorized representative. All protocol amendments will undergo the same review and 
approval process as the original protocol. A protocol amendment may be implemented only after 
it has been approved by the IRB, unless immediate implementation of the change is necessary for 
subject safety. In this case, the situation must be documented and reported to the Sponsor 
immediately and to the IRB within 5 working days.
13.8 Access to Source Documentation
The Sponsor (or the Sponsor’s authorized representative) must have access to inspect all 
documents and records that are to be maintained by the Investigator, including, but not limited 
to, medical records (office, clinic, or hospital) for the subjects in this trial. These regulations also 
allow the Sponsor’s records to be inspected by authorized representatives of the FDA or other 
regulatory authorities. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on CRFs or other records that are provided to or retained by the 
Sponsor (or the Sponsor’s authorized representative).
13.9 Financial Disclosure
Clinical Investigators are required to provide financial disclosure information to the Sponsor to 
permit the Sponsor to fulfill its obligations under 21 CFR §54. In addition, investigators must 
commit to promptly updating this information if any relevant changes occur during the study and 
for a period of 1 year after the completion of the study.
For this study, any personnel listed on the FDA 1572 Form will be required to provide financial 
disclosure information.
13.10 Publication Policy
Manuscript(s) and abstract(s) may only be prepared through cooperation between the Sponsor (or 
designee) and the study Investigator(s).
The Investigator agrees not to publish or publicly 
present any results of the study without prior written consent of the Sponsor.
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Protocol:  BPN14770-CNS-203
Tetra Discovery Partners, Inc.
Date: 25 June 2018
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Page 53 of 58
14 ADMINISTRATIVE INFORMATION
14.1 Sponsor 
Tetra Discovery Partners, Inc.
38 Fulton Street West, Suite 303
Grand Rapids, MI 4953-2684
Phone: 616.635.0937
14.2 Biological Specimens
CMIC, Inc.
2860 Forbs Avenue
Hoffman Estates, Illinois 60192-3702
Phone: 847.645.0407
Phone: 224.293.6800
Email: www.cmic-inc.com 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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Protocol:  BPN14770-CNS-203
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Date: 25 June 2018
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Page 54 of 58
15 REFERENCES
1. Declaration of Helsinki (Fortaleza, October 2013) Seventh revision, 64th World Medical
Association General Assembly Meeting.
2. International Conference on Harmonisation (ICH) E6 (R1) Good Clinical Practice
Guideline.
3. Burgin AB, Magnusson OT, Singh J, et al. Design of Phosphodiesterase Type 4D
(PDE4D) Allosteric Modulators for Cognition with Improved Safety. Nature
Biotechnology 2010; 28:63-70.
4. Fox D, 3rd, Burgin AB, Gurney ME. Structural basis for the design of selective
phosphodiesterase 4B inhibitors. Cellular signaling 2014; 26:657-63.
5. Gurney M, Cogram P, Deacon RM, Rex C, Tranfaglia M. Multiple Behavior Phenotypes of
the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of
Phosphodiesterase-4D (PDE4D). Scientific Reports 7, Article number: 14653 (2017);
doi:10.1038/s41598-017-15028-x
6. Sansone et al. Improving IQ measurement in intellectual disabilities using true deviation
from population norms. Journal of Neurodevelopmental Disorders 2014; 6:16.
7. NIH Toolbox, web address: http://www.healthmeasures.net/explore-measurement-
systems/nih-toolbox .
8. Weintraub S, Dikmen SS, Heaton RK, Tulsky DS, Zelazo PD, Bauer PJ, et al. Cognition
assessment using the NIH Toolbox. Neurology. 2013;80(11 Suppl3):S54–64.
9. Gershon RC, Cella D, Fox NA, Havlik RJ, Hendrie HC, Wagster MV. Assessment of
neurological and behavioural function: the NIH Toolbox. Lancet Neurol. 2010;9(2):138–9.
10. Hessl et al. The NIH toolbox Cognitive Battery for intellectual disabilities: three
preliminary studies and future direction. Journal of Neurodevelopmental Disorders (2016)
8:35; DOI 10.1186/s11689-016-9167-4.
11. Knox et al. Feasibility, reliability, and clinical validity of the Test of Attentional
Performance for Children (KiTAP) in Fragile X syndrome (FXS). Journal of
Neurodevelopmental Disorders. 2012; 4:2.
12. Berry-Kravis E, Sansone S, Crestodina C, McLennan Y, Chin J, Joshi R, Schneider A,
Leigh MJ, Hagerman R, Hessl D. Sensitivity of the KiTAP executive function battery and
an eye tracking paradigm to effects of AFQ056 in fragile X syndrome. Ann Neurol
2016;80:S413.
13. Berry-Kravis E, Rubin J, Harary E, Daniely Y. A 6-week, randomized, multicenter, double-
blind, parallel, flexed- and fixed-dose study of MDX (Metadoxine extended-release;
MG01CI) compared with placebo in adolescents and adults with fragile X syndrome.
American Academy of Child and Adolescent Psychiatry meeting, San Antonio, October
2015.
14. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious
behavioral problems. N Engl J Med. 2002; 347:314–321. [PubMed: 12151468].
15. Berry-Kravis E, Sumis A, Hervey C, et al. Open-label treatment trial of lithium to target the
underlying defect in fragile X syndrome. J Dev Behav Pediatr. 2008; 29:293–302.
[PubMed:18698192].
16. Guy, William (1976). "Clinical Global Impressions". ECDEU Assessment Manual for
Psychopharmacology—Revised. Rockville, MD: U.S. Department of Health, Education,
and Welfare; Public Health Service, Alcohol; Drug Abuse, and Mental Health
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Administration; National Institute of Mental Health; Psychopharmacology Research 
Branch; Division of Extramural Research Programs. pp. 218–222. OCLC 2344751. DHEW 
Publ No ADM 76–338 – via Internet Archive.
17. Berry-Kravis E, Hessl D, Rathmell B, Zarovecs P, Cherubini M, Walton-Bowen K,
Gonzales-Heydrich J, Wang P, Carpenter R, Bear M, Hagerman R. Effects of STX209
(arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a
randomized, controlled, phase 2 trial. Sci Transl Med 2012 Sep 19;4(152):152ra127.
18. Sansone SM, Widaman KF, Hall SS, et al. Psychometric Study of the Aberrant Behavior
Checklist in Fragile X Syndrome and Implications for Targeted Treatment. Journal of
Autism and Developmental Disorders. 2012;42(7):1377-1392. doi:10.1007/s10803-011-
1370-2.
19. Cordeiro, L, Ballinger E, Hagerman R and Hessl D. Clinical assessment of DSM-IV
anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodevelop
Disord. 2010; 3:9067. https://doi.org/10.1007/s11689-010-9067-y.
20. Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). Sara S. Sparrow, PhD,
Domenic V. Cicchetti, PhD, Celine A. Saulnier, PhD. Web link:
https://www.pearsonclinical.com/psychology/products/100001622/vineland-adaptive-
behavior-scales-third-edition--vineland-3.html#tab-resources.
21. Luck S. J. An Introduction to the Event-Related Potential Technique. 2005. Cambridge,
MA: MIT Press.
22. Knoth IS, Lippé S. Event-related potential alterations in fragile X syndrome. Frontiers in
Human Neuroscience. 2012;6:264. doi:10.3389/fnhum.2012.00264.
23. Ethridge et al. Neural synchronization deficits linked to cortical hyper-excitability and
auditory hypersensitivity in fragile X syndrome. Molecular Autism (2017) 8:22 DOI
10.1186/s13229-017-0140-1.
24. Farzin, F., Scaggs, F., Hervey, C. et al. Reliability of eye tracking and pupillometry
measures in individuals with Fragile X Syndrome. J Autism Dev Disord. 2011; 41:1515.
https://doi.org/10.1007/s10803-011-1176-2.
25. Method No. HP074P, Validation of an Analytical Method for the Determination of
BPN14770 in Human Plasma by High-Performance Liquid Chromatography/Tandem Mass
Spectrometry (15April2016).
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BPN14770 
Clinical Study Repo11: BPN14770-CNS-203 
Protocol: BPNl 4 770-CNS-203 
Date: 25 June 2018 
16 Appendices 
16.1 Schedule of Assessments 
Screening 
Pl 
Pl 
Days -28 
thru 0 
Day 1 
Wk 
1 
Target Day 
within each 
-28-0 
1 
7±2 
Pe1iod 
Clinic Visit 
X 
X 
Telephone Call 
X 
Informed Consent 
X 
Eligibility 
X 
Xb 
Medical /Surgical 
X 
History 
Demographic 
X 
/Social History 
Physical Exam 
X 
Abbreviated PE 
Xb 
Ht, Wt, BMI 
X 
Vital Signi 
X 
Xb 
ECGs (single) 
X 
Chemistry and 
X 
Hematology 
Urinalysis 
X 
Suicidality 
X 
X 
PK and 
Biomarker 
X 
Sampling 
Randomization 
X 
Dispense Test 
X 
Medication 
1st Dose of 
X 
Medication 
Stanford-Binet 
NIH-TCB 
X 
KiTAP 
X 
CGI-S f 
X 
CGI-I f 
VAS 
X 
ABC 
X 
ADAMS 
X 
Vineland-3f 
x• 
Confidential 
PERIOD 1 
Cross-
over 
P l 
Pl 
Pl 
Wk2 Wk6 Wk12* 
14±2 42±3 
84±3 
X 
X 
X 
x' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Tetra Discove1y Partners Inc. 
Tetra Discove1y Partners, Inc. 
Confidential 
PERIOD 2 
Follow-
Up/ 
P2 
P2 
P2 
P2 
P2 
Wk12 
P2 
Day 1* Wkl Wk 2 Wk 6 (Early 
Wkl 
Term") 
1 
7±2 
14±2 42±3 
84±3 
91±2 
X 
X 
X 
X 
X 
X 
x' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


BPN14770 
Clinical Study Repo11: BPN14770-CNS-203 
Protocol: BPNl 4 770-CNS-203 
Date: 25 June 2018 
Screening 
Days -28 
Pl 
thru 0 
Day 1 
Target Day 
within each 
-28-0 
1 
Pe1iod 
Clinic Visit 
X 
X 
Telephone Call 
ERP 
X 
Eye Tracking 
X 
IP accountability 
ConMeds 
X 
X 
Adverse Events 
X 
Final Disposition 
PERIOD 1 
Pl 
P l 
Pl 
Wk Wk2 Wk6 
1 
7±2 
14±2 42±3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pl 
Wk12* 
84±3 
X 
X 
X 
X 
X 
X 
*Note: Period 1 Wk 12 and Period 2 Day 1 visits may be combined 
Tetra Discove1y Partners Inc. 
Tetra Discove1y Partners, Inc. 
Confidential 
Cross-
PERIOD 2 
Follow-
over 
Up/ 
P2 
P2 
P2 
P2 
P2 
Wk12 
P2 
Day 1* Wk l Wk 2 Wk 6 (Early 
Wkl 
Term") 
1 
7±2 
14±2 42±3 
84±3 
91±2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• If early termination occurs, the Week 12 procedures should be completed at the time of the subject's withdrawal (if possible). 
b Do not need to repeat if screening and baseline done at same visit. 
cweight only 
d Vital signs include pulse rate, blood pressure, respiration rate, and temperature. 
e If the site has performed a Stanford-Binet test or Vineland-3 assessment on the subject in the 6 months prior to screening, the 
results of these ~ssessments may be used tor tlll.s study. 
f The CGI-S, CGI-I and Vineland-3 assessments may be conducted over the telephone, if necessary. 
Page 57 of 58 
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Page 58 of 58
16.2 Clinical Laboratory Analytes
Standard Chemistry 
Alanine aminotransferase (ALT) 
Albumin
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bicarbonate 
Blood urea nitrogen (BUN)
Calcium
Chloride
Creatinine
Glucose
Potassium
Sodium
Total bilirubin
Total protein
Hematology 
Hematocrit
Hemoglobin
Platelet count
Red blood cell (RBC)
Mean corpuscular hemoglobin concentration (MCHC)
Mean corpuscular hemoglobin (MCH)
White blood cell count and differential (basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils)
Mean corpuscular volume (MCV)
.
Urinalysis
Bilirubin
Blood
Glucose
Ketones
Nitrite
pH
Protein
Specific Gravity
Urobilinogen
Leukocyte esterase
If protein, urine occult blood, nitrite, or leukocyte esterase values are out of range, the microscopic examination will be reported. 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
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Tetra Discovery Partners Inc. 
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SAP_001.pdf: 
Statistical Analysis Plan 
Version 1.0 
Tetra Discovery Partners BPN14770-CNS-203 
16 July 2020 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN (SAP) 
Protocol Number: 
BPN14770-CNS-203 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, 2-
period Crossover Study of BPN14770 in Adult Males 
with Fragile X Syndrome 
Product Name or Number: 
BPN14770 
Sponsor: 
Tetra Discovery Partners, Inc. 
38 Fulton Street West, Suite 303 
Grand Rapids, MI 49503-2684 
SAP Prepared by: 
 
 
 
 
 
SAP Version Number (Date): 
Version 1.0 (16 July 2020) 
BPN14770 
Clinical Study Report: BPN14770-CNS-203 
_________________________________________________________
______________________________________________________________________________
Tetra Discovery Partners Inc. 
______________________________________
NCT #: NCT03569631


Statistical Analysis Plan 
Version 1.0 
Tetra Discovery Partners BPN14770-CNS-203 
16 July 2020 
CONFIDENTIAL 
2 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................4 
2 
STUDY OVERVIEW ..........................................................................................................6 
3 
STUDY OBJECTIVES ........................................................................................................8 
3.1 
Study Objectives ..............................................................................................................8 
3.2 
Exploratory Efficacy Endpoints .......................................................................................8 
3.3 
Safety and Tolerability Endpoints ...................................................................................8 
4 
GENERAL METHODS.......................................................................................................8 
4.1 
Analysis Populations ........................................................................................................8 
4.2 
Summarization of Data ....................................................................................................9 
4.3 
Sample Size Justification .................................................................................................9 
4.4 
Multiplicity ......................................................................................................................9 
4.5 
Output Production and Validation ...................................................................................9 
5 
SUBJECT DISPOSITION ...................................................................................................9 
6 
DEMOGRAPHIC CHARACTERISTICS ...........................................................................9 
7 
MEDICAL HISTORY & PHYSICAL EXAMINATION .................................................10 
8 
COGNITIVE TESTING ANALYSIS ...............................................................................10 
8.1 
NIH-Toolbox Cognition Battery (NIH-TCB) ................................................................10 
8.2 
KiTAP – Test of Attention Performance .......................................................................11 
8.3 
Clinical Global Impression Severity (CGI-S) ................................................................12 
8.4 
Clinical Global Impression Improvement (CGI-I) ........................................................12 
8.5 
Visual Analog Scale (VAS) ...........................................................................................13 
8.6 
Aberrant Behavior Checklist (ABC) ..............................................................................13 
8.7 
Anxiety Depression and Mood Scale (ADAMS) ..........................................................14 
8.8 
Event-Related Potentials (ERP) .....................................................................................14 
8.9 
Eye Tracking ..................................................................................................................16 
8.10 
Pharmacokinetics ...........................................................................................................17 
8.11 
Biomarkers (Pharmacodynamics) ..................................................................................17 
9 
SAFETY ANALYSES.......................................................................................................17 
9.1 
Adverse Events ..............................................................................................................17 
9.2 
Laboratory Tests (Hematology, Serum Chemistry, and Urinalysis) .............................18 
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Statistical Analysis Plan 
Version 1.0 
Tetra Discovery Partners BPN14770-CNS-203 
16 July 2020 
CONFIDENTIAL 
3 
9.3 
Vital Signs ......................................................................................................................18 
9.4 
Electrocardiograms ........................................................................................................18 
10 
SUBJECT LISTINGS ........................................................................................................18 
11 
INTERIM ANALYSES .....................................................................................................19 
12 
REFERENCES ..................................................................................................................20 
13 
FINAL SIGN-OFF FOR TETRA DISCOVERY PARTNERS, PROTOCOL 
BPN14770-CNS-203 STATISTICAL ANALYSIS PLAN ...............................................21 
14 
REVISIONS TO STATISTICAL ANALYSIS PLAN ......................................................22 
15 
APPENDIX ........................................................................................................................23 
15.1 
Conventions for Statistical Tables and Subject Listings ...............................................23 
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Statistical Analysis Plan 
Version 1.0 
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16 July 2020 
CONFIDENTIAL 
4 
1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
ABC-FX 
aberrant behavior checklist (fragile X-specific factoring system) 
ADAMS 
anxiety, depression, and mood scale 
AE 
adverse event 
API 
active pharmaceutical ingredient 
bid, BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BPM 
beats per minute 
CGI-I 
clinical global impression improvement – investigator rated 
CGI-S 
clinical global impression severity – investigator rated 
CNS 
central nervous system 
CP 
completer population 
CRF 
case report form 
ECG 
electrocardiogram  
ERP 
event related potential 
FDA 
food and drug administration 
FXS 
fragile X syndrome 
IRB 
institutional review board 
ITI 
inter-trial interval 
ITT 
intent to treat population 
KiTAP 
test of attentional performance 
MEDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram  
n, N 
number 
NIH-TCB 
NIH toolbox cognitive battery for intellectual disabilities  
PI 
principal investigator 
PK 
pharmacokinetic  
PO 
by mouth (per os) 
qd, QD 
once daily (every 24 hours) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
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Abbreviation or Term 
Definition 
VAS 
visual analog scale 
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2 STUDY OVERVIEW 
This is a single center, Phase 2, randomized, double-blind, placebo-controlled, 2-period 
crossover study to obtain preliminary assessment of the effects of BPN14770 in subjects with 
Fragile X Syndrome. As schematic display of the study design is shown in Figure 1.  
The study will consist of a Screening period of up to 28 days prior to initial study drug 
administration, followed by two 12-week double-blind treatment periods. The screening and the 
baseline visit for Period 1 may occur at the same time, provided the results of screening safety 
labs can be rapidly obtained. Subjects will be allowed to combine Period 1 Week 12 and Period 2 
Day 1 visits.  No washout period will be utilized between double-blind treatment periods; 
instead, efficacy and biomarker assessments during the second double-blind period (Period 2) 
will be obtained after a minimum of 6 weeks to allow for drug washout. A final follow-up phone 
contact for safety is planned one week after the conclusion of Period 2.  
Eligible patients will be randomized in a blinded, balanced (1:1) fashion to receive either 
BPN14770 25 mg bid or matching placebo during Period 1, followed by the opposite treatment 
during Period 2.  
Brief cognitive and behavioral assessments will be performed during each clinic visit. Safety and 
tolerability assessments throughout the study will include adverse event monitoring, ECGs, vital 
signs, blood chemistry, hematology, and urinalysis.  
Pharmacokinetic samples will be collected at screening and at end of Periods 1 and 2 (Week 12) 
to confirm that study drug is present when expected and to estimate plasma exposure.  Biomarker 
samples will be also collected at the time the pharmacokinetics samples are obtained. 
Study Duration 
The total duration of the study of each subject will be up to 29 weeks, including a maximum of a 
4-week screening period, two 12-week double-blind treatment periods, and a follow-up call
approximately 1 week after last treatment.
Figure 1: Study Design Schematic 
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Study Procedures 
The Screening Visit will occur up to 28 days prior to the first study drug administration on 
Day 1.  During screening, subjects and their parent/legal authorized guardian, if indicated, will 
review and sign an Informed Consent/Assent form prior to any study procedures being 
performed. Following confirmation of a prior diagnosis for Fragile X, subjects will have 
information collected regarding their neurological and medical/surgical history, race/ethnicity, 
social history (tobacco, alcohol, and/or drug use), and use of prescription and over-the-counter 
medications. Subjects will undergo a full physical exam, have vital signs measured, and 12-lead 
ECG performed.  Height, weight, and BMI will also be collected.  Fasting blood samples will be 
collected for chemistry and hematology, as well as biomarkers and pharmacokinetics. Urine will 
be collected for urinalysis. The Stanford-Binet test will also be administered at screening, as will 
an assessment of suicidality risk. 
At the Baseline visit (Period 1, Day 1), prior to randomization, patients will receive an 
abbreviated physical examination including vital signs. However, these will not be repeated if 
the Screening and Baseline visits occur on the same day. Cognitive and behavioral evaluations 
will be performed, and these measurements will be used as a common set of baseline 
measurements to which post-treatment assessments will be compared for both treatment periods. 
During both double-blind periods, subjects will receive twice-daily treatment with blinded study 
medication as randomly assigned at baseline. Doses of study medication should be taken in the 
morning and at night, at least 6 hours apart and at least 30 minutes prior to or 1 hour after meals. 
Subjects will return to the clinic at the end of Weeks 2, 6, and 12 for each period. Cognitive and 
behavioral evaluations will be repeated at Weeks 6 and 12 for each period, with the exception of 
event-related potentials and eye tracking which will be repeated only at Week 12 for each period. 
Additionally, subjects will be monitored for adverse events, changes in concurrent medications 
and suicidality via a telephone call at the end of Week 1 of each period, and one week following 
completion of Period 2 (concurrent medications and AEs only). During clinic visits, adverse 
effects will be assessed, and laboratory measures, vital signs, and ECGs will be repeated per 
protocol. Suicidality risk with also be evaluated during the treatment periods per protocol; if a 
concern is detected, the subject will be referred for further evaluation and treatment. If a patient 
discontinues the study before Week 12 of a period, the clinical site will endeavor to collect all 
assessments to be completed at Week 12. 
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3 STUDY OBJECTIVES 
3.1 Study Objectives 
The objectives in this study are: 
•
To obtain preliminary assessment of the efficacy of BPN14770 25 mg bid,
•
To evaluate the safety and tolerability of BPN14770 25 mg bid, and
•
To obtain pharmacokinetic, pharmacodynamic, and biomarker data on BPN14770.
3.2 Exploratory Efficacy Endpoints 
The following instruments will be used to assess the exploratory efficacy endpoints: 
•
NIH Toolbox Cognitive Battery Modified for Intellectual Disabilities (NIH-TCB)
•
Test of Attentional Performance (KiTAP)
•
Clinical Global Impression Severity – Investigator rated (CGI-S)
•
Clinical Global Impression Improvement – Investigator rated (CGI-I)
•
Visual Analog Scale (VAS) Rating Scale using patient-specific behavioral anchors
•
Aberrant Behavior Checklist (ABC)
•
Anxiety, Depression, and Mood Scale (ADAMS)
•
Vineland-3 Rating Scale
•
Event-Related Potentials (ERP)
•
Eye Tracking
3.3 Safety and Tolerability Endpoints 
The following safety assessments will be conducted during the study: 
•
Treatment-emergent adverse events
•
Changes in vital signs
•
Clinical laboratory evaluations (chemistry, hematology, urinalysis)
•
Electrocardiogram (ECG) measurements
4 GENERAL METHODS 
4.1 Analysis Populations 
Safety Population: All subjects who sign the study-specific informed consent documents and 
receive at least one dose of study medication.  
Intent to Treat (ITT) Population: All randomized subjects who receive at least one dose of 
treatment and return for at least one follow-up visit. 
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Completer Population (CP): All randomized subjects who complete both treatment periods 
with no significant protocol deviations. 
4.2 Summarization of Data 
Study results will be summarized by treatment group (Placebo or 25 mg BID) or treatment 
sequence (A-B, B-A), where appropriate. 
No imputation of missing data will be performed.  No windowing of visits will be performed 
unless otherwise specified. 
4.3 Sample Size Justification 
While no definitive sample size calculations were performed due to the exploratory nature of the 
study, a common standard deviation of 3 units and an effect size of 2.25 units on the Aberrant 
Behavior Checklist should provide 80% power to detect a significant difference at alpha = 0.05 
with 30 crossover subjects. If carryover effects or excessive dropouts allow only for a first Period 
analysis, a sample size of 15 per group during the first period would allow for detection of an 
effect size of 3.19 units. 
4.4 Multiplicity 
Since this is an exploratory study of BPN14770, no multiplicity adjustments will be made to any 
alpha levels used for statistical testing for efficacy endpoints.  P-values <0.05 will be used as an 
indication of treatment effect for all efficacy endpoints. 
4.5 Output Production and Validation 
All analyses will be performed using SAS V 9.3 or higher (SAS Institute, Inc, Cary, North 
Carolina, USA).  Validation and quality control of the tables and listings, which display the 
results of the statistical analysis of the data from this study, will follow the appropriate 
 standard operating procedures (SOPs). 
5 SUBJECT DISPOSITION 
The number of subjects who are in the safety population, who completed the study, and who 
discontinued from the study, along with reason of study discontinuation, will be summarized in 
tabular format by treatment sequence and all subjects for the safety population.  Subject 
disposition information will be displayed for the safety population in a subject listing. 
6 DEMOGRAPHIC CHARACTERISTICS 
For quantitative variables (e.g., age, height, weight, body mass index [BMI], and Stanford-Binet 
Full Intelligence scale), summary statistics (number [n], mean, standard deviation [SD], 
minimum, median, and maximum) will be presented by treatment sequence and all subjects for 
the safety population.  For the qualitative variables (e.g., sex, race, and ethnicity), results will be 
summarized by treatment group as counts and percentages for the safety population.  Individual 
demographic information for the safety population will be displayed in subject listings.  
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7 MEDICAL HISTORY & PHYSICAL EXAMINATION 
Medical history, physical examination findings and neurological examination findings will be 
displayed for the safety population in a subject listing.
8 COGNITIVE TESTING ANALYSIS 
8.1 NIH-Toolbox Cognition Battery (NIH-TCB) 
The NIH-TCB is a battery of extensively validated computer-administered cognitive tests with 
utility across childhood and adolescence, early adulthood, and old age. The NIH-TCB 
assessments were designed to minimize floor and ceiling effects which often are present in 
testing batteries designed for the general population. Downward extensions of many of the NIH-
TCB tests have been created to allow feasibility down to a mental age of 3. Therefore, there is 
good reason to believe that the assessments are appropriate for individuals with intellectual 
disabilities. 
NIH-TCB includes the following evaluations/composite scores: 
•
Picture Vocabulary
•
Oral Reading Recognition
•
List Sorting Working Memory
•
Pattern Comparison Processing Speed
•
Picture Sequence Memory
•
Flanker Inhibitory Control and Attention
•
Dimensional Change Card Set
•
Cognition Crystallized Composite Score
•
Cognition Fluid Composite Score
•
Cognition Total Composite Score
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values and the change-from-baseline values to each posttreatment 
time point for the uncorrected standard scores, the dext raw scores, and the dext raw percentages 
if available for each of the above evaluations/composite scores for the ITT population and the 
completer population.  In these displays, baseline will be defined as the last non-missing value 
obtained prior to first dose of study medication for Period 1, Day 1 predose 
The primary uncorrected standard scores are the uncorrected standard scores for cognition 
crystallized composite, picture vocabulary, oral reading recognition, pattern comparison 
processing speed, and picture sequence memory.  The primary uncorrected standard scores will 
be analyzed using a mixed effect model.  The change from baseline will be used in the model as 
the dependent variable.  The model will include sequence, period, treatment, visit, predose 
baseline NIH-TCB, baseline Stanford-Binet Full IQ score, and visit by treatment interaction as 
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fixed effects, with subject within sequence as a random effect. This analysis will be done for 
both the ITT population and the completer population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline NIH-TCB 
and baseline Stanford-Binet Full IQ covariates for the ITT population for the primary 
uncorrected standard scores. 
If a subject could not complete the uncorrected standard flanker control and attention test then 
the Downward extension was to be used. The same method was to be used for the uncorrected 
standard dimensional change card sort test. Since the Downward extension scores are not the 
same as the uncorrected standard scores, they could not be used in the calculations for the 
cognition fluid composite score or the cognition total composite score.    Therefore, the above 
tests will be denoted as secondary uncorrected standard scores and only summary statistics will 
be provided. 
For the uncorrected standard list sorting working memory score, it was observed that more than 
50% of the subjects had missing data at baseline and/or at week 12 after approximately 2/3 of the 
subjects had completed Period 1.  If this trend of sparsity of data remains upon completion of the 
study, the uncorrected standard list sorting working memory score will also be denoted as a 
secondary uncorrected standard score and only summary statistics will be provided.  
The NIH-TCB results will be displayed in subject listings. 
8.2 KiTAP – Test of Attention Performance 
KiTAP consists of eight nonverbal subtests measuring different basal as well as higher-order 
components of attention and executive functioning.  Four subtests (i.e., alertness, distractibility, 
go-nogo, and flexibility) will be utilized in the study.  Within each subtest, mean reaction time, 
standard deviation time, number correct, number error, and number omissions were reported as 
appropriate.   
The primary endpoints are the alertness mean reaction time, distractibility correct (distractor), 
distractibility errors (distractor), flexibility correct, flexibility errors, go-nogo correct, and 
go-nogo errors.  Summary statistics (n, mean, standard deviation, minimum, median, and 
maximum) will be presented for the observed values and the change-from-baseline values to 
each posttreatment time point for the primary endpoints for the ITT population and the completer 
population.  In these displays, baseline will be defined as the last non-missing value obtained 
prior to first dose of study medication for Period 1, Day 1 predose. 
The primary endpoints will be analyzed using a mixed effect model.  The change from baseline 
will be used in the model as the dependent variable.  The model will include sequence, period, 
treatment, visit, predose baseline KiTAP score, baseline Stanford-Binet Full IQ score, and visit 
by treatment interaction as fixed effects, with subject within sequence as a random effect. This 
analysis will be done for both the ITT population and the completer population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline KiTAP and 
baseline Stanford-Binet full IQ covariates for the ITT population for the primary endpoints. 
All KiTAP assessments will be displayed in subject listings. 
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8.3 Clinical Global Impression Severity (CGI-S) 
CGI-S is a global measure to provide a clinical judgment of a subject’s overall condition based 
on a trained clinician’s assessment of cognition, behavior and activities of daily living.  The 
assessment of severity will be made with a 7-point scale: 1, not ill; 2, very mild; 3, mild; 4, 
moderate; 5, marked; 6, severe; 7, extremely severe. 
CGI-S will be summarized by treatment group as counts and percentages at each visit for the ITT 
population and the completer population.  In addition, CGI-S will be summarized by treatment 
group as counts and percentages at each visit for the Period 1 data only.  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values and the change-from-baseline values to each posttreatment 
time point for CGI-S for the ITT population and the completer population.  In these displays, 
baseline will be defined as the last non-missing value obtained prior to first dose of study 
medication for Period 1, Day 1 predose. 
CGI-S will be analyzed using a mixed effect model.  The change from baseline will be used in 
the model as the dependent variable.  The model will include sequence, period, treatment, visit, 
predose baseline CGI-S score, baseline Stanford-Binet Full IQ score, and visit by treatment 
interaction as fixed effects, with subject within sequence as a random effect. This analysis will 
be done for both the ITT population and the completer population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline CGI-S and 
baseline Stanford-Binet full IQ covariates for the ITT population for CGI-S. 
The CGI-S results will be displayed in subject listings. 
8.4 Clinical Global Impression Improvement (CGI-I) 
CGI-I assessment is a 7-point scale that requires the clinician to assess how much the subject's 
illness has improved or worsened relative to a baseline state at the beginning of the intervention, 
and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 
5, minimally worse; 6, much worse; or 7, very much worse. 
CGI-I will be summarized by treatment group as counts and percentages at each visit for the ITT 
population and the completer population.  In addition, CGI-I will be summarized by treatment 
group as counts and percentages at each visit for the Period 1 data only.  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values at each posttreatment time point for CGI-I for the ITT 
population and the completer population.   
CGI-I will be analyzed using a mixed effect model and will be used in the model as the 
dependent variable.  The model will include sequence, period, treatment, visit, baseline Stanford-
Binet Full IQ score, and visit by treatment interaction as fixed effects, with subject within 
sequence as a random effect. This analysis will be done for both the ITT population and the 
completer population. 
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In addition, for Period 1 data only, CGI-I will be analyzed using an analysis of covariance 
(ANCOVA) model with fixed terms for treatment, and baseline Stanford-Binet full IQ covariates 
for the ITT population at Week 12. 
The CGI-I results will be displayed in subject listings. 
8.5 Visual Analog Scale (VAS) 
VAS consists of three domains:  daily functioning, anxiety/irritability, and irritability/language.  
For each of the domains, the parents/caregiver will mark on a visual line measuring 10 cm with 
one side marked “worst behavior” and the other side marked “best behavior.”  The 
parents/caregiver marks are measured in millimeter distance so that improvements or worsening 
of behavior over the treatment period can be evaluated.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values and the change-from-baseline values to each posttreatment 
time point for each of the three domains for the ITT population and the completer population.  In 
these displays, baseline will be defined as the last non-missing value obtained prior to first dose 
of study medication for Period 1, Day 1 predose. 
The three domains of the VAS will each be analyzed using a mixed effect model.  The change 
from baseline will be used in the model as the dependent variable.  The model will include 
sequence, period, treatment, visit, predose baseline VAS score, baseline Stanford-Binet Full IQ 
score, and visit by treatment interaction as fixed effects, with subject within sequence as a 
random effect. This analysis will be done for both the ITT population and the completer 
population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline VAS and 
baseline Stanford-Binet full IQ covariates for the ITT population for each domain. 
The VAS results will be displayed in subject listings. 
8.6 Aberrant Behavior Checklist (ABC) 
ABC is a 58-item parent/caregiver rating scale used to assess behaviors across six dimensions or 
subscales:  irritability, hyperactivity, lethargy/withdrawal, stereotypy, inappropriate speech and 
social avoidance. Items are evaluated on a four-point Likert scale ranging from 0 (not at all a 
problem) to 3 (the problem is severe in degree).    
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values and the change-from-baseline values to each posttreatment 
time point for each of the six subscales for the ITT population and the completer population.  In 
these displays, baseline will be defined as the last non-missing value obtained prior to first dose 
of study medication for Period 1, Day 1 predose. 
For each subscale, the change-from-baseline to Week 12 will be analyzed using an analysis of 
covariance (ANCOVA) model which includes sequence, period, and treatment as fixed factors, 
subject within sequence as a random factor, and baseline ABC score and baseline Stanford-Binet 
full IQ covariates for the ITT population and the completer population. 
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In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline ABC and 
baseline Stanford-Binet full IQ covariates for the ITT population for each subscale. 
All ABC assessments will be displayed in subject listings. 
8.7 Anxiety Depression and Mood Scale (ADAMS) 
ADAMS is a 28-item behavior-based informant instrument rated by the parent/caregiver and 
designed to assess anxiety, depression, and mood disorders in individuals with intellectual 
disability.  Items are rated on a scale of 0 (“behavior has not occurred or is not a problem”) to 3 
(“behavior occurs a lot or is a severe problem”).  The scale is composed of 5 factors which 
address: Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety and 
Obsessive/Compulsive Behavior.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values and the change-from-baseline values to each posttreatment 
time point for each of the five factors for the ITT population and the completer population.  In 
these displays, baseline will be defined as the last non-missing value obtained prior to first dose 
of study medication for Period 1, Day 1 predose. 
For each factor, the change-from-baseline to Week 12 will be analyzed using an analysis of 
covariance (ANCOVA) model which includes sequence, period, and treatment as fixed factors, 
subject within sequence as a random factor, and baseline ADAMS score and baseline Stanford-
Binet full IQ covariates for the ITT population and the completer population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline ADAMS 
and baseline Stanford-Binet full IQ covariates for the ITT population for each factor. 
All ADAMS results will be displayed in subject listings. 
8.8 Event-Related Potentials (ERP) 
Event-related Potentials (ERPs) enable extraction of neural responses associated with specific 
sensory, cognitive, or motor events from an overall EEG as cited in the protocol.  Auditory 
stimuli are presented and EEG events assessed in relation to timing of the stimuli.  For this study, 
an ERP protocol developed to measure auditory habituation to trains of repeated stimuli, resting 
state delta power, and oddball task responses in FXS will be used (Ethridge et al, 2017). This 
ERP protocol has shown feasibility and clinical validity based on comparison to sensory 
hypersensitivity on the Sensory Profile in FXS. The EEGs will be read by 
 
who developed the ERP protocol and has extensive experience in ERP evaluation.  
 
will reject data if there is too much artifact present (i.e., the amount of usable data is below a 
50% threshold determined by the total number of trials). 
The following parameters will be accessed: 
1. Habituation
•
N1 amplitude to first paired stimulus
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o
FXS typically show increased N1 amplitude to auditory stimuli relative to
typically developing controls. It is expected that the N1 amplitude will
decrease as a sign of positive impact.
•
N1 amplitude to second paired stimulus
o
FXS typically show increased N1 amplitude to auditory stimuli relative to
typically developing controls, and in particular show a lack of reduction of N1
amplitude in response to repeated stimuli in a stimulus pair. It is expected that
the N1 amplitude to the repeated stimulus will decrease as a sign of positive
impact.
•
N1 amplitude percent change between first and second paired stimulus
o
This is the amount of amplitude decrease (i.e. the amount of habituation) of
the N1 ERP from first stimulus to second (repeated) stimulus in the pair,
calculated as a ratio to control for individual differences in absolute ERP
amplitude. It is expected that this ratio will increase as a sign of positive
impact.
2.
Oddball
•
P2 amplitude standard condition
o
FXS typically show increased P2 amplitude to auditory stimuli relative to
typically developing controls. It is expected that P2 amplitude will decrease as
a sign of positive impact.
•
P2 amplitude oddball condition
o
FXS typically show increased P2 amplitude to auditory stimuli relative to
typically developing controls, but less differentiation between standard and
oddball stimulus in amplitude. It is expected that P2 amplitude will decrease
as a sign of positive impact.
•
P2 amplitude percent change between oddball and standard condition
o
FXS typically show increased P2 amplitude to auditory stimuli relative to
typically developing controls, but less differentiation between standard and
oddball stimulus in amplitude. Typically developing individuals show
increased P2 amplitude to oddball stimuli relative to standard stimuli. It is
expected that the ratio of P2 amplitude between standard and oddball stimuli
in FXS will increase as a sign of positive impact.
3.
Resting
•
Ratio of occipital alpha power during eyes closed condition during resting EEG
o
Typically developing individuals show increased occipital alpha power during
eyes closed resting EEG compared to eyes open resting EEG, whereas FXS
show less differentiation between the two conditions. It is expected that an
increase in the ratio of eyes closed to eyes open alpha power in FXS as a sign
of positive impact.
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•
Resting gamma power across whole head during eyes open condition
o
FXS typically show increased gamma power during rest compared to typically
developing controls. It is expected that a decrease in gamma power as a sign
of positive impact.
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the above values and the change-from-baseline values to each posttreatment time 
point for each of the eight parameters for the ITT population and the completer population.  In 
these displays, baseline will be defined as the last non-missing value obtained prior to first dose 
of study medication for Period 1, Day 1 predose. 
For each parameter, the change-from-baseline to Week 12 will be analyzed using an analysis of 
covariance (ANCOVA) model which includes sequence, period, and treatment as fixed factors, 
subject within sequence as a random factor, and baseline ERP score and baseline Stanford-Binet 
full IQ covariates for the ITT population and the completer population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline ERP and 
baseline Stanford-Binet full IQ covariates for the ITT population for each factor and the overall 
score. 
All ERP results will be displayed in subject listings. 
8.9 Eye Tracking 
Eye tracking will be used to assess social gaze in the subjects. Testing will be conducted in a 
quiet room with the lights turned off. The eye tracker (Tobii) will be calibrated for each subject 
at the beginning of each session. Following calibration, subjects will view pictures shown on the 
screen. Each assessment begins with presentation of a scrambled face image for 1 s followed 
immediately by its matched face image for 3 s. An inter-trial interval containing a uniform grey 
screen is shown for 0.5, 1, or 2 s, randomly determined. The order of face presentation is 
pseudorandomized and each eye tracking session lasts approximately 6 min.  Measurements will 
be the number of fixations and the proportion of looking time (%) for the following regions of 
interest:  eyes, nose, mouth, and other.  An increased in the number of fixations within the eye 
region and an increase in the proportion of looking time (%) within the eye region indicates an 
improvement within a subject.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the above values and the change-from-baseline values to each posttreatment time 
point for each of the above parameters for the ITT population and the completer population.  In 
these displays, baseline will be defined as the last non-missing value obtained prior to first dose 
of study medication for Period 1, Day 1 predose. 
For each parameter, the change-from-baseline to Week 12 will be analyzed using an analysis of 
covariance (ANCOVA) model which includes sequence, period, and treatment as fixed factors, 
subject within sequence as a random factor, and baseline eye tracking score and baseline 
Stanford-Binet full IQ covariates for the ITT population and the completer population. 
In addition, for Period 1 data only, the change-from-baseline to Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model with fixed terms for treatment, baseline eye 
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tracking and baseline Stanford-Binet full IQ covariates for the ITT population for each 
parameter. 
The data displays may be modified based on the actual data received for the analysis. 
Eye tracking results will be displayed in subject listings. 
8.10 Pharmacokinetics 
The pharmacokinetic concentrations will be displayed in summary tables as well as in the subject 
listings. 
8.11 Biomarkers (Pharmacodynamics) 
A description of the biomarkers analysis is not included in this statistical analysis plan.  The 
biomarker analysis, if conducted, will be exploratory and determined by the clinical results 
observed in the study. 
9 SAFETY ANALYSES 
9.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (using MedDRA version stated in Data Management Plan).  An overall summary 
table will be presented by treatment group that summarizes all treatment-emergent adverse 
events, all serious treatment-emergent adverse events, all study drug-related treatment-emergent 
adverse events as assessed by PI, all study drug discontinuations due to treatment-emergent 
adverse events, number of deaths, and all severe treatment-emergent adverse events for the 
safety population.  In addition, a frequency table will be presented by treatment group for all 
treatment-emergent adverse events by system organ class and preferred term for number and 
percentage of subjects: 
•
by maximum severity
•
by relationship to study drug
An adverse event will be considered to be treatment-emergent for the treatment given in Period 1 
if the event first appears after initial dosing in Period 1 or if it is a pre-existing condition that 
worsens following initial dosing through Period 2, Day 1.  An adverse event will be considered 
to be treatment-emergent for the treatment given in Period 2 if the event first appears after Period 
2, Day 1 or if it is a pre-existing condition worsens after Period 2, Day 1.  Because the start time 
of adverse events is not collected on the case report form, it will be assumed that any TEAEs 
reported as starting on Period 2 Day 1 will be assigned to the treatment from Period 1.  Any 
medical condition/event already present prior to the subject taking the first dose of study 
treatment will be reported in the medical history.  Subject listings of all treatment-emergent 
adverse events will be provided.   
In all displays, adverse events will be displayed by MedDRA System Organ Class and Preferred 
Terms, with subjects who have the same adverse event counted only once for that event and with 
subjects who have more than one adverse event within a System Organ Class counted only once 
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in that System Organ Class.  An adverse event will be considered drug-related if, in the 
investigator’s judgment, the event was related to treatment. 
9.2 
Laboratory Tests (Hematology, Serum Chemistry, and Urinalysis) 
For hematology, chemistry, and urinalysis quantitative tests, summary statistics (n, mean, SD, 
minimum, median, and maximum) will be presented for the observed values at each time point 
by treatment group for the safety population.  Summary statistics will also be presented for the 
change-from-baseline values to each post baseline time point.  In these displays, baseline will be 
defined as the last non-missing value obtained prior to first dose of study medication for Period 
1, Day 1 predose. 
For all tests, results will be displayed in subject listings, with those values falling outside the 
laboratory reference range flagged.  Laboratory reference ranges will be provided by the 
laboratory site(s) and will be included in an appendix of the clinical study report. 
9.3 Vital Signs 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be presented for the 
observed values for sitting systolic and diastolic blood pressure, pulse, respiration rate, and oral 
temperature at baseline and each post dose time point by treatment group for the safety 
population.  Summary statistics will also be presented for the change-from-baseline values to 
each post baseline time point.  In these displays, baseline will be defined as the last non-missing 
value obtained prior to first dose of study medication for Period 1, Day 1 predose. 
All vital signs results will be displayed in subject listings. 
9.4 Electrocardiograms 
Single ECG results will be collected at Baseline/Screening and at Week 6 and Week 12 of each 
study period.  For the quantitative variables of QRS interval, PR interval, QT interval, QTcB 
interval, and Heart Rate, summary statistics (n, mean, SD, minimum, median, and maximum) 
will be presented for the observed values at Baseline/Screening and each post dose time point.  
Summary statistics will also be presented for change-from-baseline values to each post baseline 
time point.  In these displays, baseline will be defined as the last non-missing value obtained 
prior to first dose of study medication for Period 1, Day 1 predose.   
All ECG results will be displayed in subject listings. 
10 SUBJECT LISTINGS 
Data that are collected and entered into the study database but that are not displayed in the 
summary tables specified in the preceding sections will be presented in subject listings.  These 
will include (but will not be limited to) data from the following data collection modules: 
Protocol Deviations 
Drug Accountability/Dosing Information 
Inclusion/Exclusion Criteria 
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Caregiver Information 
Concomitant Medications 
Concomitant Treatments/Procedures 
Stanford-Binet Non-Verbal and Verbal Intelligence Scale 
Substance Abuse 
Suicidality Assessment 
11 INTERIM ANALYSES 
No statistical interim analyses are planned. 
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12 REFERENCES 
Ethridge et al. Neural synchronization deficits linked to cortical hyper-excitability and auditory 
hypersensitivity in fragile X syndrome. Molecular Autism (2017) 8:22 DOI 10.1186/s13229-
017-0140-1.
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13 FINAL SIGN-OFF FOR TETRA DISCOVERY PARTNERS, 
PROTOCOL BPN14770-CNS-203 STATISTICAL ANALYSIS PLAN 
 
 
 
 
Date 
 
 
Tetra Discovery Partners, Inc. 
Grand Rapids, MI 49503-2684 
Date 
Tetra Discovery Partners, Inc. 
Grand Rapids, MI 49503-2684 
Date 
13-Aug-2020 | 9:08 AM EDT
14-Aug-2020 | 10:40 AM PDT
14-Aug-2020 | 1:15 PM PDT
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14 REVISIONS TO STATISTICAL ANALYSIS PLAN 
Date 
Revision 
Statistician’s Signature 
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15 APPENDIX 
15.1 Conventions for Statistical Tables and Subject Listings 
The following conventions are used in the mockups for the statistical tables and subject listings: 
[Sponsor] = [Tetra Discovery Partners] 
[Protocol] = [BPN14770-CNS-203] 
[Drug name] = [BPN14770] 
Subject number in listings will represent the subject’s screening number. 
In general, font size will be at least 9-point and all margins will be 1 inch. 
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