Conditions: Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 255
Healthy volunteers: no

Brief summary:
A Randomized, Double-blind, Placebo Controlled, 3-Arm Parallel Design Study to Evaluate the Effects of BPN14770 in Patients with Early Alzheimer's Disease

Detailed description:

Arms:
arm 1: 10 mg bid dose of the Drug BPN14770 arm 2: 25mg bid dose of the Drug BPN14770 arm 3: None

Interventions: intervention 1: BPN14770 intervention 2: Placebo
Intervention descriptions: intervention 1: Drug BPN14770 intervention 2: Placebo

Protocol document:
Prot_002.pdf: 
Page 1 of 61 
Clinical Trial Protocol: BPN14770-CNS-201 
Title 
A 
Randomized, 
Double-blind, 
Placebo-
controlled, 3-Arm Parallel Design Study to 
Evaluate the Effects of BPN14770 in Patients 
with Early Stage Alzheimer’s Disease   
Substance Identifier 
BPN14770 
IND Number 
127905 
Indication 
Treatment of Alzheimer’s Disease 
Phase 
Phase 2 
Sponsor 
Tetra Discovery Partners, Inc. 
Sponsor Contact 
 
Tetra Discovery Partners, Inc. 
38 Fulton Street West Suite 303 
Grand Rapids, MI 49503-2684 
Principal Investigator 
TBD 
Amendment 
Revision Date 
Reason 
N/A 
21 December 2018 
Original submission 
2.0 
25 February 2019 
Incorporation of clarifications; update to eligibility 
criteria 
3.0 
24 September 2019 
Incorporation of additional clarifications, including 
eligibility criteria 
Confidentiality Statement 
This document contains information that is confidential and proprietary to the Sponsor, Tetra Discovery 
Partners, Inc..  This information is being provided to you solely for the purpose of evaluating and/or 
conducting a clinical trial for the Sponsor.  You may disclose the contents of this document only to 
study personnel under your supervision, the Institutional Review Board, the United States Food and 
Drug Administration, or duly authorized representatives of regulatory agencies for this purpose 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, you will give prompt notice to the Sponsor of any such disclosure. 
NCT03817684


Protocol:  BPN14770-CNS-201 
 
 
   Tetra Discovery Partners, Inc. 
Date:  24 September 2019 
 
  Confidential 
 
Page 2 of 61 
1 SIGNATURES 
1.1 Sponsor Signatures 
 
Protocol Number: 
BPN14770-CNS-201  
Sponsor: 
Tetra Discovery Partners, Inc. 
Sponsor Contact: 
 
Tetra Discovery Partners, Inc. 
 
38 Fulton Street West, Suite 303 
 
Grand Rapids, MI 4953-2684 
 
Phone: 
 
 
 
 
(Signature) 
(Date) 
 
 
Study Director & 
Medical Monitor 
 
Tetra Discovery Partners, Inc. 
 
38 Fulton Street West, Suite 303 
 
Grand Rapids, MI 4953-2684 
 
Phone:
 
 
 
 
(Signature) 
(Date) 
 
 
 
 
 
 
25Sept2019
9/27/2019


Protocol:  BPN14770-CNS-201 
 
 
   Tetra Discovery Partners, Inc. 
Date:  24 September 2019 
 
  Confidential 
 
Page 3 of 61 
1.2 Investigator Signature 
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. I 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 Helsinki.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 312 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: 
 
 
 
 
 
 
 
(Signature) 
(Date) 
 
 
 


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 4 of 61 
SYNOPSIS 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
Study Phase: 
Phase 2 
Study Objectives: 
 
In subjects with a clinical diagnosis of early stage Alzheimer’s disease (AD) receiving cholinesterase inhibitor 
therapy: 
• 
To evaluate the efficacy of two dose levels (10 mg bid and 25 mg bid) of BPN14770  
• 
To evaluate the safety and tolerability of BPN14770 10 and 25 mg bid 
• 
To obtain pharmacokinetic data on BPN14770 in this subject population 
 
Overview of Endpoints  
 
Primary Efficacy Endpoint:   
• 
Repeatable Battery for the Assessment of Neurological Status - Delayed Memory Index (RBANS DMI) – 
change from baseline assessed at Week 13 
 
Secondary Efficacy Endpoints  
• 
RBANS total score 
• 
Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL ) total score 
• 
Mini-Mental State Exam (MMSE) score 
• 
Clinical Dementia Rating sum of boxes score (CDR-SB) 
• 
Clinical Global Impression – Improvement (CGI-I) 
• 
Composite endpoint based on AD Composite Score (ADCOMS) 
 
Safety and Tolerability: The safety variables to be assessed include adverse events; clinical laboratory parameters 
(chemistry, hematology, lipids, 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 during the Weeks 1, 4, 8 and 13 clinic 
visits.  Samples will be drawn according to 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 (PK) samples will be 
retained and may also be utilized subsequently for biomarker assessment.  
 
Biomarkers: Blood samples will also be obtained for biomarker testing, at Baseline (Day 1) and at Weeks 1, 4, 8 
and 13.  Samples will be frozen and retained with the PK plasma samples and may be utilized subsequently for 
biomarker assessment.   
 
Study Design: 
This is a Phase 2, randomized, double-blind, placebo-controlled, 3-arm, parallel-design study to evaluate the effects 
of BPN14770 in subjects with a clinical diagnosis of early stage AD. The study will consist of a Screening period 
of up to 28 days prior to initial study drug administration, a 13-week double-blind treatment, and a final follow-up 
visit for safety one week after treatment is concluded.   
 
Randomization will be stratified based on presence or absence of an ApoE4 allele in the patient’s genetic profile. 
Within each stratum, subjects will be randomized in a blinded, balanced fashion to receive either BPN14770 10mg 
bid, BPN14770 25 mg bid, or matching placebo.  


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 5 of 61 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
Study Phase: 
Phase 2 
 
Subjects will have a total of eight clinic visits: Screening; Baseline (Day 1); Weeks 1, 2, 4, 8, 13, and the final 
Follow-up Visit. Cognitive testing will be performed during each clinic visit except the final Follow-up Visit. 
Safety and tolerability assessments throughout the study will include adverse event monitoring, ECGs, vital signs, 
blood chemistry, hematology; urinalysis will be performed at Screening, Baseline, and Weeks 1, 4, and 13, and 
lipid evaluations at Baseline and Week 13.  Should gastrointestinal (GI) side effects occur, nausea may be treated 
with 5-HT3 antagonists, and diarrhea may be treated with loperamide.  Anticholinergic drugs may not be used to 
treat GI side effects. 
 
Pharmacokinetic samples will be collected during the treatment period to confirm that study drug is present, and to 
estimate plasma exposure at Weeks 1, 4, 8 and 13.   
 
An independent data and safety monitoring board (DSMB) will provide safety oversight for this study.  The DSMB 
will consist of two qualified MDs and one statistician.  The DSMB will review standard safety data approximately 
every four (4) months, based on enrollment rate.  A DSMB charter will be developed to further outline the DSMB 
responsibilities and the desired listings, summaries and analyses.    
Planned Numbers of Subjects: 
A target of 80 evaluable subjects per group (240 total) is planned.  Approximately 85 subjects per group will be 
enrolled (255 total) in order to account for potential dropouts.   
 


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 6 of 61 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
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, subjects will sign the informed consent form prior to any study procedures being performed.  Following 
a positive clinical diagnosis for early stage AD, 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.  Either a blood sample or buccal swab will be obtained for 
genetic testing for the ApoE4 allele if testing was not previously performed and documented for the subject.  [Note: 
previous ApoE4 genetic testing results must be reviewed by study personnel].  Subjects will undergo a full physical 
exam and have vital signs and 12-lead ECG measured.  Height, weight, and BMI will also be collected (or 
calculated in the case of BMI).  Blood samples will be obtained for chemistry and hematology. Urine will be 
collected for urinalysis.  Other eligibility criteria assessed during the screening period include serology (HbsAg, 
HCV); Columbia-Suicide Severity Rating Scale (C-SSRS) assessment; screening, diagnostic assessment of early 
stage AD, and MMSE for eligibility.  
 
At the Baseline visit (Day 1), prior to drug administration, subjects will receive an abbreviated physical 
examination and ECG.  Fasting blood samples for blood chemistry, hematology, lipid testing and biomarkers will 
be obtained. A serum pregnancy test will be conducted for females of childbearing potential.  Randomization will 
be stratified based on presence or absence of an ApoE4 allele following the baseline assessments.  
 
During the Double-Blind period, subjects will receive twice-daily treatment with blinded study medication.  Doses 
of study medication should be taken in the morning and at night, approximately 12 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 1, 2, 4, 8, and 13, and for a follow-up safety visit 
approximately one week after completing the Double-Blind period. Fasting blood samples will be collected at the 
Week 13 visit.  During clinic visits, adverse effects will be assessed, and laboratory measures, vital signs, and ECG 
will be repeated according to the Schedule of Assessments.  Efficacy measures will be obtained to measure the 
effects of BPN14770 on cognition as well as functional status at Weeks 1, 2, 4, 8, and 13.  Every effort will be 
made to retain each subject throughout the entire study period; however, if a subject must be withdrawn prior to 
Week 13, all Week 13 safety assessments should be completed, if possible. 
 
 
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. Males or females between the ages of 55 and 85 years (inclusive) with a clinical diagnosis of early stage AD, 
defined according to the following criteria assessed prior to randomization:  
a) Clinical Dementia Rating (CDR) score of 0.5 or 1, with Memory Box score of 0.5 or greater 
b) MMSE score of 20 or greater 
c) RBANS DMI score ≤ 85  
 
Note:  PET imaging for amyloid is not required for diagnosis, which will be made on clinical grounds. 
2. Currently receiving a stable dose regimen of donepezil or another cholinesterase inhibitor for treatment of 


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 7 of 61 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
Study Phase: 
Phase 2 
Alzheimer’s disease. Subjects must be receiving a stable dose of a cholinesterase inhibitor for at least 56 days 
prior to their baseline visit. Doses of these drugs may not be changed during the trial.   
 
       Note: Memantine is not permitted during the trial and must be discontinued at least 3 weeks prior to 
Baseline. 
3. Modified Hachinski Ischemia score < 4. 
4. Body mass index (BMI) < 38 kg/m2, inclusive, and body weight of >48 kg (105 pounds) at screening. 
5. Female subjects must be at least two years post-menopausal (subjected reported menopausal status), surgically 
sterile (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months prior to first study 
drug administration), or willing to either (1) utilize hormonal contraception plus one barrier method or (2) use 
two barrier methods of contraception (e.g. diaphragm and spermicide) from initial screening until one month 
after taking the final dose.  An intrauterine device (IUD) is considered a barrier method of contraception in this 
study. Male subjects must be willing to inform female partners of their participation in the study and must 
agree to use adequate contraceptive methods (vasectomy performed at least 6 months prior to first study drug 
administration, or use at least one barrier method of birth control) from initial screening until one month after 
taking the final dose.   
6. Able to understand and comply with the study procedures, voluntarily agree to participate in this study, read 
the informed consent document, and provide written informed consent prior to start of any study-specific 
procedures. If the subject is unable to read the consent form and provide written  consent, a legally authorized 
representative of the subject may read and sign the informed consent and the subject must verbally assent to 
participation. 
7. All subjects must have a caregiver who is willing and able to ensure compliance with study medications, visits, 
and study procedures.    
 
Subject Exclusion Criteria 
The following Exclusions apply to findings during Screening or at Baseline (Day 1) 
1. Any medical or neurological condition (other than early stage AD) that might be a contributing cause to the 
subject’s cognitive impairment, including prominent features of Lewy body dementia, behavioral variant 
frontotemporal dementia, semantic variant primary progressive aphasia or nonfluent/agrammatic variant 
primary progressive aphasia. 
2. No substantial concomitant cerebrovascular disease, defined by a history of stroke temporally related to the 
onset or worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white 
matter hyperintensity burden on imaging. 
3. No evidence for another concurrent, active neurological disease, or a non-neurologic medical co-morbidity or 
use of medication that could have a substantial effect on cognition. 
4. Clinically significant major psychiatric illness during the past 6 months, as determined by the Investigator. 
5. History of unstable angina, myocardial infarction, chronic heart failure, or clinically significant conduction 
abnormalities during the past year. 
6. Clinically significant liver or renal disease, defined as creatinine clearance <30 mL/min at screening. 
7. Clinically significant abnormality, in the Investigator’s judgment, in hematology, chemistry, or urinalysis. 
8. Positive serology results for hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV).  HCV subjects 
who have been treated and are now RNA negative are eligible to participate. 
9. Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine aminotransferase >2 
× the upper limit of normal [ULN], or total bilirubin >1.7 × ULN, based on appropriate age and gender normal 
values). Subjects with Gilbert’s syndrome are eligible to participate despite elevated bilirubin. Subjects may be 
re-screened for these tests once.   
10. Marked hypotension (systolic blood pressure [BP] ˂90 mmHg or diastolic BP ˂50 mmHg) or hypertension 


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 8 of 61 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
Study Phase: 
Phase 2 
(systolic BP ˃160 mmHg or diastolic BP ˃100 mmHg) based on sitting values.  Out-of-range results may be 
repeated once at Screening and Baseline, if needed. Eligibility must be confirmed at Baseline. 
11. Marked bradycardia (heart rate ˂45 beats per minute [bpm]) or tachycardia (heart rate ˃115 bpm) based on 
supine ECG values.  Out-of-range results may be repeated once at Screening and at Baseline, if needed. 
Eligibility must be confirmed at Baseline. 
12. Presence of any clinically important conduction abnormality(ies) as assessed by Investigator on ECG, or 
evidence  of long QT syndrome based on supine ECG values obtained at Screening, or history of long QT 
syndrome based on supine ECG values.  Clinically important out-of-range results may be repeated once. 
Eligibility must be confirmed at Baseline. 
13. Active gastric or duodenal ulcers or other diseases of the gastrointestinal tract that could interfere with 
absorption of study drug.  Note: Subjects with a history of appendectomy or cholecystectomy may be enrolled, 
as may subjects with gastric bypass, gastric sleeve, of controlled inflammatory bowel. 
14. Active acute or chronic infectious diseases that would interfere with subject’s participation in the study.    
15. Patients who cannot discontinue the following centrally active medications that might interfere with cognitive 
assessments are excluded.  These include: 
a. 
Anticonvulsants 
b. Memantine  
c. 
Antipsychotic drugs, tricyclic antidepressants, gabapentin, and pregabalin 
d. Stimulants including modafinil 
e. 
Daytime use of benzodiazepines (bedtime use of benzodiazepines is permitted)   
 
Note: The following medications are permitted provided the dosage and dose regimen have been stable for 2 
months and remain stable throughout the study: 
a. 
Cholinesterase inhibitors as per protocol 
b. SSRIs, SNRIs, and bupropion  
c. 
Beta-blockers 
d. Hypnotics for sleep, including benzodiazepines, non-benzodiazapines (Ambien, Lunesta), 
antihistamines, hydroxyzine and trazodone. Other medications that are often used for sleep such 
as mirtazapine and quetiapine are not permitted.   
e. 
Benadryl (diphenhydramine) and other sedating antihistamines are permitted only at bedtime for 
night time sleep management.   
16. Patients who cannot discontinue strong CYP450 2D6 and 3A4/3A5/3A7 enzyme inducers at least 14 days prior 
to the first dose of study drug are excluded. Specifically, this includes rifampin, barbituates, and 
carbamazepine. CYP450 2D6 and 3A4/3A5/3A7 inhibitors are permitted.  
17. Note: Other prescription or non-prescription drugs necessary for the patient’s welfare, such as antihypertensive 
or cholesterol lowering agents are allowed, if, in the Investigator’s judgement, they would not interfere with 
the study medication or the cognitive testing.A suicidal ideation intensity score of 3 or higher per screening 
Columbia Suicide Severity Rating Scale (C-SSRS) assessment on Day 1 (Baseline) and/or any suicidal 
behavior within the past 3 months. 
18. History of chronic alcohol or other substance abuse, including marijuana, within the previous year prior to the 
Screening visit (per the current edition of the Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition: DSM-5), or regular (daily) consumption of alcohol exceeding two bottles of beer, or the equivalent 
amount of other forms of alcohol (1 serving = 12 oz beer, 5.0 oz wine, or 1.5 oz distilled spirits). 
19. Inability or unwillingness to comply with the protocol, including performing the cognitive function tests, or 
likely inability to complete the study. 


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 9 of 61 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
Study Phase: 
Phase 2 
20. Participation in other clinical studies involving investigational drug within the previous 30 days prior to the 
Screening Visit. Participation in other clinical trials of monoclonal antibody products requires a 90-day wash 
out period prior to the screening visit. 
21. Donation of blood within 4 weeks, or blood products within 2 weeks, prior to first study drug administration. 
22. History of clinically significant drug allergy that includes symptoms such as shortness of breath, rash, or 
edema.   
23. Clinically significant B12 deficiency within 12 months prior to Visit 1 (Screening), based on clinical diagnosis. 
Participants on stable replacement therapy for a minimum of 3 consecutive months immediately prior to 
screening may be included. 
 
Investigational Product, Dosage, and Mode of Administration:   
In this randomized double-blind, placebo-controlled 3-arm parallel study, 255 subjects will be randomized (1:1:1) 
to receive one of the following three treatments (85 per group), in addition to receiving their ongoing treatment 
with a cholinesterase inhibitor: 
 
• 
BPN14770 10 mg bid 
• 
BPN14770 25 mg bid 
• 
Matching Placebo 
 
All study medications will be provided as identical-appearing HPMC capsules in HPE bottles.  Study drug will be 
taken by mouth (PO) with water (at least 120 mL = 4 ounces) in the morning and at night, approximately 12 hours 
apart, and at least 30 minutes prior to or 1 hour after meals.   
Statistical Analyses: 
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 
per protocol (PP) population (randomized subjects who received at least one dose of treatment and returned for at 
least one follow-up visit with no significant protocol violations) and the completers (CP) population (randomized 
subjects who completed all 13 weeks of treatment with no significant protocol violations) will be used to evaluate 
the robustness of the ITT results. 
 
Change from baseline will be calculated for the primary and secondary efficacy parameters at each time point and 
descriptive statistics provided for each time point. Summary plots of these data will also be provided. For RBANS 
DMI and total score, MMSE score, and ADCS-ADL total score, pairwise differences in change from baseline 
between the treatment groups (10 mg vs 25 mg BPN14770, 10 mg BPN14770 vs Placebo, 25 mg BPN14770 vs 
Placebo) will be assessed using an analysis of covariance (ANCOVA) model that includes baseline as a covariate 
and factors for week, site and treatment and the interaction term for week and treatment; the pairwise differences 
will be assessed at each time point.  CDR sum of boxes will be analyzed in the same manner.  
 
Change from baseline in the other RBANS index scores (immediate memory, visuospatial/constructional, attention, 
language) will be summarized by time point, with descriptive statistics provided. 
 
The composite endpoint will be based on the AD Composite Score (ADCOMS), a composite clinical outcome for 
prodromal Alzheimer's disease trials.20 The composite endpoint and analysis model will be fully specified in the 
statistical analysis plan. 
 
The efficacy analyses will be performed on the ITT, PP and CP analysis populations. 


Protocol:  BPN14770-CNS-201 
Tetra Discovery Partners, Inc. 
Date: 24 September 2019 
Confidential 
Page 10 of 61 
Name of Sponsor/Company: 
Tetra Discovery Partners, Inc. 
Name of Investigational Product: 
BPN14770 
Study Title:   
A Randomized, Double-blind, Placebo-controlled, 3-Arm 
Parallel Design Study to Evaluate the Effects of BPN14770 in 
Patients with Early Stage Alzheimer’s Disease   
Study Number: 
BPN14770-CNS-201 
Study Phase: 
Phase 2 
Supplemental analyses assessing treatment effect relative to severity of disease based on baseline MMSE score may 
also be performed. 
 
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 as assessed by the Investigator, 
will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) and AE severity and 
relatedness to treatment will be assessed. AEs will be tabulated for each of the treatment groups separately, as well 
as for all BPN14770 recipients combined. 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. 
 
For each AE, the difference in incidence rates between the each BPN14770 dose group will be compared to the 
placebo group using a Fisher’s exact test.   
Sample Size Determination: 
This study will enroll 255 subjects (85 per treatment arm), in anticipation of evaluating at least 240 subjects (80 per 
treatment). Based on 80 subjects per group completing the study, the probability is 80 percent that the study will 
detect a treatment difference at a two-sided 0.05 significance level, if the true difference between BPN14770 25 mg 
and placebo is 7.15 units. Using the standardized mean difference (SMD) to estimate effect size, a change of 7.15 
units on the DMI score is an effect size of 0.45.    
 
 


Protocol:  BPN14770-CNS-201 
 
 
   Tetra Discovery Partners, Inc. 
Date:  24 September 2019 
 
  Confidential 
 
Page 11 of 61 
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 
21 
4.3.2.1 
BPN14770-CNS-101 
21 
4.3.2.2 
BPN14770-CNS-102 
21 
4.3.2.3 
BPN14770-CNS-103 
23 
4.4 
Study Objectives and Endpoints 
23 
4.4.1 
Study Objectives 
23 
4.4.2 
Efficacy Endpoints 
24 
4.4.2.1 
Primary Efficacy Outcome Measure 
24 
4.4.2.2 
Secondary Efficacy Outcome Measures 
24 
4.4.3 
Safety and Tolerability Endpoints 
24 
4.4.4 
Pharmacokinetic Endpoints 
24 
5 
INVESTIGATIONAL PLAN 
24 
5.1 
Overall Study Design 
24 
5.2 
Dose Selection 
25 
5.3 
Study Duration 
25 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS 
25 
6.1 
Study Population 
25 
6.2 
Subject Inclusion Criteria 
26 
6.3 
Subject Exclusion Criteria 
26 
6.4 
Subject Withdrawal 
29 
6.5 
Replacement of Subjects 
29 
7 
TREATMENT OF SUBJECTS 
29 
7.1 
Treatment Arms 
29 
7.2 
Study Medications 
30 
7.3 
Drug Accountability 
30 
7.4 
Blinding 
30 


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Date: 24 September 2019 
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Page 12 of 61 
7.5 
Assignment of Subjects to Treatment Arms 
31 
7.6 
Study Drug Administration 
31 
7.7 
Prior and Concomitant Medications 
31 
7.8 
Dietary Guidelines 
32 
7.9 
Lifestyle Guidelines 
32 
8 
STUDY PROCEDURES AND ASSESSMENTS 
32 
8.1 
Informed Consent 
32 
8.2 
Medical /Surgical History 
32 
8.3 
Demographics and Social History 
32 
8.4 
Physical Examination (Full and Abbreviated) 
32 
8.5 
Height, Weight, Body Mass Index 
33 
8.6 
Vital Signs 
33 
8.7 
Electrocardiograms 
34 
8.8 
Laboratory Assessments 
34 
8.9 
Management of Abnormal Clinical Laboratory Tests 
34 
8.10 
Columbia Suicide Severity Rating Scale (C-SSRS) 
34 
8.11 
Additional Safety Measures 
35 
8.12 
Cognitive Battery 
35 
8.13 
Clinical Global Impression- Improvement 
35 
8.14 
Pharmacokinetic Assessment 
36 
8.14.1 
Plasma Pharmacokinetic Samples 
36 
8.14.2 
Processing and Shipment of Pharmacokinetic Samples 
36 
8.14.2.1 
Standard Pharmacokinetic Sampling 
36 
8.14.2.2 
Metabolite Sampling at Week 13 (select sites) 
37 
8.14.3 
Analytical Methods 
37 
8.14.4 
Plasma Pharmacokinetic Parameters 
37 
8.15 
Biomarker Assessments 
37 
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 


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9.3.4 
Reporting Serious Adverse Events 
41 
9.4 
Data Safety and Monitoring Committee 
42 
9.5 
Reports of Pregnancy 
43 
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 (Day 1) 
44 
10.4 
Week 1 (Day 7 ± 2) 
44 
10.5 
Week 2 (Day 14 ± 2) 
45 
10.6 
Week 4 (Day 28 ± 2) 
45 
10.7 
Week 8 (Day 56 ± 3) 
45 
10.8 
Week 13 (Day 91 ± 3) 
46 
10.9 
Week 14 Follow-up Visit (Day 98 ± 3) 
46 
10.10 Early Termination 
46 
11 PLANNED STATISTICAL METHODS 
47 
11.1 
Sample Size 
47 
11.2 
Demographics 
48 
11.3 
Analysis Populations 
48 
11.4 
Efficacy: Cognitive Testing Analysis 
49 
11.5 
Safety Analysis 
49 
11.6 
Pharmacokinetic Analysis 
49 
12 DATA MANAGEMENT 
50 
12.1 
Data Handling 
50 
12.2 
Computer Systems 
50 
12.3 
Data Entry 
50 
12.4 
Medical Information Coding 
50 
12.5 
Data Validation 
50 
13 INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
50 
13.1 
Ethical Conduct of the Study 
50 
13.2 
Institutional Review Board (IRB) 
51 
13.3 
Informed Consent 
51 
13.4 
Study Monitoring 
52 
13.5 
Disclosure of Information 
52 
13.6 
Record Storage and Retention 
53 
13.7 
Protocol Amendments and Deviations 
53 
13.8 
Access to Source Documentation 
54 
13.9 
Financial Disclosure 
54 


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13.10 Publication Policy 
54 
14 ADMINISTRATIVE INFORMATION 
54 
14.1 
Sponsor 
54 
14.2 
Clinical Research Organization 
54 
15 REFERENCES 
55 
16 APPENDICES 
57 
16.1 
Schedule of Assessments 
57 
16.2 
Clinical Laboratory Analytes 
59 
16.3 
Cognitive Test Scales 
60 
16.3.1 
RBANS 
60 
16.3.2 
MMSE 
60 
16.3.3 
ADCS-ADL 
60 
16.3.4 
CDR 
60 
16.3.5 
Modified Hachinski Ischemia Score (MHIS) 
60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 LIST OF ABBREVIATIONS  
AD 
Alzheimer’s disease 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Inventory -  
ADR 
Adverse drug reaction 
AE(s) 
Adverse event(s) 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
API 
Active pharmaceutical ingredient 
ApoE4 
Apolipoprotein E4  
BDNF 
Brain-derived neurotrophic factor 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
Beats per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees centigrade 
cAMP 
3’-5’- cyclic adenosine monophosphate 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating – Sum of Boxes 
CGI-I 
Clinical Global Impression - Improvement 
CNS 
Central nervous system 
CREB 
cAMP response element binding 
CRF 
Case report form 
eCRF 
Electronic case report form 
CRO 
Clinical research organization  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
EH 
hepatic extraction ratio 
FDA 
Food and Drug Administration 
gm 
Gram 
GCP 
Good Clinical Practice 


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GI 
gastrointestinal 
hERG 
human Ether-à-go-go-Related Gene 
HDPE 
High density polyethylene 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methylcellulose 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
kg 
kilogram 
MAD 
Multiple ascending dose 
MED 
Minimum effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mg 
Milligram 
MHIS-NACC 
Modified Hachinski Ischemic Scale - NACC Version 
mL 
Milliliter 
MMSE 
Mini Mental State Exam 
msec 
Millisecond 
MTD 
Maximum tolerated dose 
NAM 
Negative allosteric modulator 
ng 
nanogram 
NOAEL 
No observed adverse effect level  
NOR 
Novel Object Recognition 
oz 
ounce  
PDE4 
phosphodiesterase type-4 
PDE4D 
phosphodiesterase type-4 subtype D 
PDE4D-NAM 
phosphodiesterase type-4D-negative allosteric modulator 
PK 
Pharmacokinetic 


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PO 
By mouth (per os) 
QTc 
Corrected QT interval 
RBANS (DMI) 
Repeatable Battery for the Assessment of Neurological Status (Delayed 
Memory Index) 
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
sc 
Subcutaneous 
SD 
Standard deviation 
SOP 
Standard operating procedure 
Tmax 
Time to maximum concentration 
µ 
Micro 
ULN 
Upper limit of normal 
USP-NF 
The United States Pharmacopeia and The National Formulary 


Protocol:  BPN14770-CNS-201 
 
 
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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.   
Since the introduction of cholinesterase inhibitors to address the depletion of acetylcholine in the 
Alzheimer’s brain (1995) and memantine to improve glutamatergic signaling (2003), there have 
been no new drugs to treat the condition.  Attempts to develop disease-modifying therapies have 
focused mainly on the amyloid pathway.3,4 This pathway has medical and genetic support but so 
far has proved challenging for therapeutic development.  Also of concern is that successful 
disease modifying therapeutics, if they slow Alzheimer’s disease (AD) progression, are unlikely 
to reverse the cognitive impairment caused by the disease.  Thus there is a need for new drugs to 
address cognitive impairment in AD and other dementias, as well as a need to find drugs that 
may help restore cognitive function and improve brain resilience to the damage caused by AD. 
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).5,6 The PDE4D enzyme subtype is a highly 
validated CNS target for improving cognition.7 
BPN14770 is a novel, selective small molecule inhibitor of the PDE4D enzyme, which is 
considered to play a role in modulating the 3’- 5’- cyclic adenosine monophosphate pathway 
(cAMP) in the brain important for learning and memory.  BPN14770 is in clinical development 
for treating alzheimer’s disease.  This is the fourth clinical study evaluating its effects in humans; 
the first study was the single dose escalation study (BPN14770-CNS-101; clinicaltrials.gov 
NCT02648672), the second was a multiple dose escalation study in healthy volunteers 
(BPN14770-CNS-102; clinicaltrials.gov NCT02840279), and the third study was single-dose, 6-
period crossover study in healthy volunteers to evaluate the effects of BPN14770 on 
scopolamine-induced cognitive impairment (BPN14770-CNS-103; NCT03030105). 
4.2 Rationale 
As of February 27, 2017, 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 ≤ 55 years of age and 30 
(22%) were ≥60 years of age. 
The single dose escalation study (-101) in 24 subjects ≤ 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 ≤45 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 ≤45 years of age received 75mg 


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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.   
In the dose escalation study (-102), there was evidence of greater than proportional increases in 
BPN14770 exposure after a single dose or repeated dosing. Drug accumulation was 
approximately 2-fold after QD dosing. After BID dosing, moderate drug accumulation of 
approximately 3- to 5-fold was observed. Steady state appeared to be reached within 2 to 4 days 
of BID or QD dosing. When adjusted for differences in dose, mean BPN14770 exposure 
appeared to be similar between healthy young and healthy elderly subjects. 
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. 
In this initial Phase 2, randomized double-blind, placebo-controlled 3-arm parallel study, 255 
subjects will be randomized (1:1:1) to receive one of the following three treatments (85 per 
group): BPN14770 10 mg bid, BPN14770 25 mg bid, matching placebo bid. Steady state 
exposure at the 25 mg dose is estimated to be at least 3-fold higher than at the 10 mg dose. The 
objectives of the study are to evaluate the efficacy and safety of the two doses of BPN 14770, as 
well as to obtain PK data to correlate with cognitive and safety outcomes. This study will assess 
two doses of BPN14770, 10 mg and 25 mg, both administered twice daily. These doses are well 
below the maximum tolerated single dose of 100 mg determined in the initial single dose study (-
101), and also are below the maximum twice daily dose of 50 mg that was well tolerated in the 
multiple dose study (-102),  and are therefore expected to be safe and well-tolerated in this trial 
in subjects with AD.  Based on accumulation data from the multiple-dose study, the exposure 
difference between the 10 and 25 mg doses should be 4-fold.   
4.3 Risk/Benefit 
4.3.1 Preclinical Pharmacology 
BPN14770 is a first-in-class, subtype selective, phosphodiesterase type-4D (PDE4D)-allosteric 
inhibitor. The unique mechanism of action and subtype selectivity distinguishes BPN14770 from 
the two approved PDE4 inhibitors, roflumilast (Daliresp™) and apremilast (Otezla™).  
Roflumilast and apremilast are competitive inhibitors that inhibit the PDE4 enzymes by binding 
in the active site competitively with 3’- 5’- cyclic adenosine monophosphate (cAMP).  As the 
amino acid sequence of the PDE4 active site is conserved between the four subtypes, roflumilast 
and apremilast inhibit all subtypes of PDE4 equally strongly.  Both compounds cause emesis in 
humans and other species, and as a class, PDE4 competitive inhibitors have been found to cause 
mesenteric vasculopathy in rats, dogs and primates, although this toxicity has not been observed 
in humans.  In contrast, BPN14770 does not bind to the active site of the PDE4 enzyme and does 


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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 has cognitive benefit in the mouse Novel Object Recognition (NOR) test at >0.3 
mg/kg by PO, as shown by an increase in the Discrimination Index.  BPN14770 maximum 
plasma concentration (Cmax) at the minimum effective dose (MED) was 160 ng/mL (in plasma) 
and 40 ng/gm (in brain).  Cognitive benefit is maintained after chronic dosing for 7 days.  
BPN14770 also has benefit in a mouse model of cholinergic impairment, the scopolamine-
impaired Y-maze (male C57Bl6 mice MED = 1 mg/kg).   
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 
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. 
 


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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 (≤45 years; n=18 treated, 7 placebo) received twice-daily doses of 15 mg, 30 mg, 
50 mg or placebo for 8 days.  Elderly subjects (≥60 years; 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.  
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 


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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%). Likewise, 
the percentage of subjects with at least one drug-related adverse event was also higher for the 40-mg 
BID dose group (70%) compared with the 10-mg BID dose group (40%), the 20-mg BID dose group 
(20%), and the placebo group (26.7%).  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%).  Across the elderly subject cohorts, 2 adverse 
events (dizziness and hypotension) of moderate severity were reported in 1 of the 10 subjects 
(10.0%) in the 10 mg BID dose group, and 1 headache of moderate severity was reported in 1 of 10 
subjects (10.0%) in the 40-mg BID dose group.  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. After a single oral dose of BPN14770 in healthy 
young subjects, Cmax and AUC12 appeared to increase in a dose-proportional fashion over the dose 
range of 15 to 50 mg, with a greater than proportional increase in exposure observed after a 75-mg 
dose. 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.  
 
After a single oral dose of BPN14770 in healthy elderly subjects, Cmax appeared to increase in a 
greater than dose-proportional fashion over the dose range of 10 to 40 mg, whereas AUC12 appeared 
to increase in a greater than dose-proportional fashion from 10 mg or 20 mg to 40 mg. Following 
BID dosing of BPN14770 in healthy elderly subjects, Cmax and AUC12 appeared to increase in a 
greater than dose-proportional fashion over the dose range of 10 to 40 mg. A moderate degree of 
accumulation (up to approximately 4-fold) was observed after BID dosing in healthy elderly subjects.  
 
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%.  


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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 
reversing scopolamine effects was also evaluated. A total of 38 subjects were enrolled into the 
study. The study duration was up to 12 weeks with 6 weeks of single-dose treatment visits. The 
study consisted of a screening visit (up to 28 days prior to first study drug administration), 6 
inpatient treatment visits (Periods 1 through 6), and a follow-up/early termination visit (7 to 10 
days after the last dose of study drug). An additional study visit may have been necessary to 
complete the required cognitive test familiarization if not completed during the screening visit. 
Each treatment visit occurred approximately 1 week apart, allowing a 6 to 8 day washout period. 
Subjects were randomized to 1 of 6 treatment sequences, each containing the 6 following 
treatments: 
A. Scopolamine placebo + BPN14770 placebo + donepezil placebo 
B. Scopolamine 0.5 mg + BPN14770 placebo + donepezil placebo 
C. Scopolamine 0.5 mg + BPN14770 10 mg + donepezil placebo 
D. Scopolamine 0.5 mg + BPN14770 50 mg + donepezil placebo 
E. Scopolamine 0.5 mg + BPN14770 placebo + donepezil 10 mg 
F. Scopolamine 0.5 mg + BPN14770 50 mg + donepezil 10 mg 
 
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 10 mg was safe and generally well tolerated when administered with scopolamine 
in healthy subjects. BPN14770 50 mg was generally safe when administered with scopolamine, 
or with scopolamine and donepezil 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. None of the TEAEs that were 
reported in this study were out of the ordinary or unexpected in clinical nature or character for 
this population of healthy subjects.  The administration of BPN14770 with donepezil did not 
appreciably increase the incidence of adverse GI side effects associated with donepezil alone.   
4.4 Study Objectives and Endpoints  
4.4.1 Study Objectives 
In subjects with a clinical diagnosis of early stage Alzheimer’s disease receiving cholinesterase 
inhibitor therapy: 
• To evaluate the efficacy of two dose levels (10 mg bid and 25 mg bid) of BPN14770  


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• To evaluate the safety and tolerability of BPN14770 10 and 25 mg bid 
• To obtain pharmacokinetic data on BPN14770 in this subject population 
4.4.2 Efficacy Endpoints 
4.4.2.1 Primary Efficacy Outcome Measure 
The primary efficacy outcome measure is the change from baseline to Week 13 in Repeatable 
Battery for the Assessment of Neurological Status - Delayed Memory Index (RBANS DMI) 
4.4.2.2 Secondary Efficacy Outcome Measures 
There are six secondary efficacy outcomes of interest. Change from baseline will be evaluated 
for each of the outcome measures below. 
• RBANS total score 
• Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory - Mild 
Cognitive Impairment version (ADCS-ADL) total score 
• Mini-Mental State Evaluation (MMSE) score 
• Clinical Dementia Rating sum of boxes (CDR-SB) score 
• Clinical Global Impression- Improvement (CGI-I) score 
• Composite endpoint based on AD Composite Score (ADCOMS) 
4.4.3 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, lipids, urinalysis)  
• Electrocardiogram (ECG) measurements 
 
4.4.4 Pharmacokinetic Endpoints 
Plasma BPN14770 concentrations at Weeks 1, 4, 8, and 13, to verify that study drug is present 
and to estimate plasma exposure at these time points.   
5 INVESTIGATIONAL PLAN 
5.1 Overall Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, 3-arm, parallel-design study to 
evaluate the effects of BPN14770 in 255 subjects with a clinical diagnosis of early stage AD. 
The study will consist of a Screening period of 28 days or less, unless additional time is required 
for washout of concomitant medications. The Screening period will be followed by a 13-week 
double-blind treatment period, and a final follow-up visit for safety one week after treatment is 
concluded. 


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Randomization will be stratified based on presence or absence of an ApoE4 allele in the 
subject’s genetic profile. Within each stratum, subjects will be randomized in a blinded, balanced 
fashion to receive either BPN14770 10mg bid, BPN14770 25 mg bid, or matching placebo. In 
total 255 subjects will be randomized (i.e., 85 subjects per treatment arm).  
Subjects will have a total of eight clinic visits: Screening; Baseline (Day 1); Weeks 1, 2, 4, 8, 13, 
and the final Follow-up Visit. The screening visit will consist of consenting the subject, 
obtaining a medical history, full physical exam, height, weight, BMI, ECG, serology testing, 
chemistry, hematology, urinalysis, ApoE4 testing,  pregnancy testing, and cognitive assessments. 
If the subject fully qualifies for the study, randomization will occur at the Baseline visit when the 
subject will receive study medication. 
Cognitive testing will occur at each visit except the final Follow-up Visit.  Safety assessments 
will also be performed at each visit, to include adverse event monitoring, vital signs, ECG, and 
chemistry and hematology. Urinalysis will also be performed at Screening and Baseline and 
Weeks 1, 4 and 13. Lipid testing will be performed at Baseline and Week 13. Risk of suicidality 
will be assessed at Screening, Baseline and Weeks 1, 4, and 13. 
Pharmacokinetic testing will occur at the clinic visits at Weeks 1, 4, 8 and 13.   
5.2 Dose Selection 
Doses of 10 and 25 mg BPN14770 to be taken twice daily were chosen for testing in this study.   
Based on pharmacokinetic data from study BPN14770-CNS-102 (MAD), steady state average 
plasma concentrations of BPN14770 10 mg 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, and 
is estimated to produce steady state with projected average plasma levels of concentrations over 
200 ng/ml.  The twice-daily doses of 10 mg and 25mg selected for this study both fall well 
within the tolerance limits defined by the SAD and MAD studies.  
5.3 Study Duration 
The total duration of the study for each subject will be up to 127 days (18 weeks), including a 
maximum of a 28-day screening period, 13 weeks of dosing, and a follow-up period (7 days after 
last dose). 
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.  Continued subject eligibility will be verified at Baseline, 
prior to randomization. 


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6.2 Subject Inclusion Criteria 
 
1. Males or females between the ages of 55 and 85 years with a clinical diagnosis of early 
stage AD, defined according to the following criteria assessed prior to randomization:  
o Clinical Dementia Rating (CDR) score of 0.5 or 1, with Memory Box score of 0.5 
or greater 
o  MMSE score of 20 or greater 
o RBANS DMI score < 85 
Note:  PET imaging for amyloid is not required for diagnosis, which will be made on 
clinical grounds 
 
2. Currently receiving a stable dose regimen of donepezil or another cholinesterase inhibitor 
for treatment of AD. Subjects must be receiving a stable dose of a cholinesterase inhibitor 
for at least 56 days prior to their baseline visit. Doses of these drugs may not be changed 
during the trial.   
Note: Memantine is not permitted during the trial and must be discontinued at least 3 
weeks prior to Baseline 
 
3. Modified Hachinski Ischemia score < 4. 
4. Body mass index (BMI) ≤38 kg/m2, inclusive, and body weight of >48 kg (105 pounds) 
at screening. 
5. Female subjects must be at least two years post-menopausal (subjected reported 
menopausal status), surgically sterile (bilateral tubal ligation, hysterectomy, or bilateral 
oophorectomy at least 6 months prior to first study drug administration), or willing to 
either (1) utilize hormonal contraception plus one barrier method or (2) use two barrier 
methods of contraception (e.g. diaphragm and spermicide) from initial screening until 
one month after taking the final dose.  An intrauterine device (IUD) is considered a 
barrier method of contraception in this study. Male subjects must be willing to inform 
female partners of their participation in the study and must agree to use adequate 
contraceptive methods (vasectomy performed at least 6 months prior to first study drug 
administration, or use at least one barrier method of birth control) from initial screening 
until 1 month after taking the final dose.   
6. Able to understand and comply with the study procedures, voluntarily agree to participate 
in this study, read the informed consent document, and provide written informed consent 
prior to start of any study-specific procedures If the subject is unable to read the consent 
form and provide written consent, a legally authorized representative of the subject may 
read and sign the informed consent and the subject must verbally assent to participation. 
7. All subjects must have a caregiver who is willing and able to ensure compliance with 
study medications, visits, and study procedures.    
6.3 Subject Exclusion Criteria 
The following Exclusions apply to findings during Screening or at Baseline (Day 1): 
 
1. Any medical or neurological condition (other than early stage AD) that might be a 
contributing cause to the subject’s cognitive impairment, including prominent features of 


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Lewy body dementia, behavioral variant frontotemporal dementia, semantic variant primary 
progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia. 
2. No substantial concomitant cerebrovascular disease, defined by a history of stroke temporally 
related to the onset or worsening of cognitive impairment; or the presence of multiple or 
extensive infarcts or severe white matter hyperintensity burden on imaging. 
3. No evidence for another concurrent, active neurological disease, or a non-neurologic medical 
co-morbidity or use of medication that could have a substantial effect on cognition. 
4. Clinically significant major psychiatric illness during the past 6 months, as determined by the 
Investigator. 
5. History of unstable angina, myocardial infarction, chronic heart failure, or clinically 
significant conduction abnormalities during the past year. 
6. Clinically significant liver or renal disease, defined as creatinine clearance <30 mL/min at 
screening. 
7. Clinically significant abnormality, in the Investigator’s judgment, in hematology, chemistry, 
or urinalysis. 
8. Positive serology results for hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV).   
HCV subjects who have been treated and are now RNA negative are eligible to participate. 
9. Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine 
aminotransferase >2 × the upper limit of normal [ULN], or total bilirubin >1.7 × ULN, based 
on appropriate age and gender normal values).  Subjects with Gilbert’s syndrome are eligible 
to participate despite elevated bilirubin. . Subjects may be re-screened for these tests once.   
10. Marked hypotension (systolic blood pressure [BP] ˂90 mmHg or diastolic BP ˂50 mmHg) or 
hypertension (systolic BP ˃160 mmHg or diastolic BP ˃100 mmHg) based on sitting values.  
Out-of-range results may be repeated once at Screening and at Baseline, if needed. Eligibility 
must be confirmed at Baseline. 
11. Marked bradycardia (heart rate ˂45 beats per minute [bpm]) or tachycardia (heart rate ˃115 
bpm) based on supine ECG values.  Out-of-range results may be repeated once at Screening. 
Eligibility must be confirmed at Baseline. 
12. Presence of any clinically important conduction abnormality(ies) as assessed by Investigator 
on ECG, or evidence  of long QT syndrome based on supine ECG values obtained at 
Screening, or history of long QT syndrome based on supine ECG values.  Clinically 
important out-of-range results may be repeated once. Eligibility must be confirmed at 
Baseline. 
13. Active gastric or duodenal ulcers or other diseases of the gastrointestinal tract that could 
interfere with absorption of study drug.  Note: Subjects with a history of appendectomy or 
cholecystectomy may be enrolled,  as may subjects with gastric bypass, gastric sleeve, of 
controlled inflammatory bowel. 
14. Active acute or chronic infectious diseases that would interfere with subject’s participation in 
the study. 
15. Patients who cannot discontinue the following centrally active medications that might 
interfere with cognitive assessments are excluded.  These include: 
a. Anticonvulsants 
b. Memantine  
c. Antipsychotic drugs, tricyclic antidepressants, gabapentin, and pregabalin 
d. Stimulants including modafinil 
e. Daytime use of benzodiazepines (bedtime use of benzodiazepines is permitted)  


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Note: The following medications are permitted provided the dosage and dose regimen 
have been stable for 2 months and remain stable throughout the study: 
a. Cholinesterase inhibitors  
b. Antidepressants other than tricyclics, including SSRIs, SNRIs, and bupropion 
c. Beta-blockers 
d. Hypnotics for sleep, including benzodiazepines, non-benzodiazapines (Ambien, 
Lunesta), antihistamines, hydroxyzine and trazadone. Other medications that are 
often used for sleep such as mirtazapine and quetiapine are not permitted.  
e. Benadryl (diphenhydramine) and other sedating antihistamines are permitted only 
at bedtime for night time sleep management. 
 
16. Patients who cannot discontinue strong CYP450 2D6 and 3A4/3A5/3A7 enzyme inducers at 
least 14 days prior to the first dose of study drug are excluded. Specifically, this includes 
rifampin, barbituates, and carbamazepine. CYP450 2D6 and 3A4/3A5/3A7 inhibitors are 
permitted. 
 
Note: Other prescription or non-prescription drugs necessary for the patient’s welfare, such 
as antihypertensive or cholesterol lowering agents are allowed, if, in the Investigator’s 
judgement, they would not interfere with the study medication or the cognitive testing.  
 
17. A suicidal ideation intensity score of 3 or higher per screening Columbia Suicide Severity 
Rating Scale (C-SSRS) assessment on Day 1 (Baseline) and/or any suicidal behavior within 
the past 3 months. 
18. History of chronic alcohol or other substance abuse, including marijuana, within the previous 
year prior to the Screening visit (per the current edition of the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition: DSM-5), or regular (daily) consumption of alcohol 
exceeding two bottles of beer, or the equivalent amount of other forms of alcohol (1 serving 
= 12 oz beer, 5.0 oz wine, or 1.5 oz distilled spirits). 
19. Inability or unwillingness to comply with the protocol, including performing the cognitive 
function tests, or likely inability to complete the study. 
20. Participation in other clinical studies involving investigational drug within the previous 30 
days prior to the Screening Visit.  Participation in other clinical trials of monoclonal antibody 
products requires a 90-day wash out period prior to the Screening Visit. 
21. Donation of blood within 4 weeks, or blood products within 2 weeks, prior to first study drug 
administration. 
22. History of clinically significant drug allergy that includes symptoms such as shortness of 
breath, rash, or edema.   
23. Clinically significant B12 deficiency based on clinical diagnosis within 12 months prior to 
Screening. Participants on stable replacement therapy for a minimum of 3 consecutive 
months immediately prior to Screening may be included. 
 


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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: 
• Subject withdraws consent or requests discontinuation from the study for any reason; 
• 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; 
• 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; 
• Pregnancy; 
• Requirement for prohibited concomitant medication; 
• 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 13 procedures (see Section 
10.3 Week 13) 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 a screen failure.  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, 3-arm, parallel group study, 255 subjects 
will be assigned to receive one of three treatments via balanced randomization (1:1:1). 
Randomization will occur separately within each ApoE4 stratum (presence/absence of ApoE4 
isoform) to ensure similar numbers of ApoE4 positive subjects are present in each treatment 
group. The three treatments are: 


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A. BPN14770 10mg,  twice-daily  
B. BPN14770 25mg, twice-daily 
C. Matched placebo, twice daily  
7.2 Study Medications 
The 10 mg and 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 (San Diego, CA).   
 
The 10 mg and 25 mg BPN14770 capsules are manufactured using a wet granulation process.  
The same granulation is used to manufacture both strengths of capsules by adjusting the amount 
of granulation. 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 34-count in 
60 cc, white, high-density polyethylene (HDPE), round bottles with 33 mm, with white 
polypropylene ribbed caps; 12-count bottles are similarly packaged.  Over the course of the 
study, each subject will receive six 34-count bottles and one 12-count bottle.  The container-
closure system is labeled with a study-specific label and stored at controlled room temperature 
(20ºC – 25ºC) in a secured location (locked) with access restricted to authorized personnel only.  
Storage temperature will be monitored and recorded.    
 
BPN14770 placebo capsules are manufactured, packaged, labeled and stored similarly to the 
active capsules. 
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. 


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Randomization codes for a specific subject will be available to the Investigator or designee for 
use in case of an emergency code break requirement.  Confirmation of release of the unblinded 
treatment designation will be required by the Sponsor.  The PI or designee 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 
bottle of medication that same day.  
7.6 Study Drug Administration 
Study drug will be taken by mouth (PO) with water (at least 120 mL = 4 ounces) in the morning 
and before bed, approximately 12 hours apart, and at least 30 minutes prior to or 1 hour after 
meals. The first dose should be taken one hour after dinner on Day 1.  
7.7 Prior and Concomitant Medications 
All concomitant medication taken 14-days prior to the first dose of study drug (Day 1) and 
during the study through the Week 14 Follow-up Visit should be recorded with indication, daily 
dose, and start and stop dates of administration. 
Subjects are required to be on a stable dosing regimen of donepezil or another cholinesterase 
inhibitor for at least 2 months, i.e., 56 days prior, to their Baseline visit. Doses of these 
medications may not change during the study. 
Memantine is not permitted during the trial and must be discontinued at least 3 weeks (21 days) 
prior to Baseline. Subjects are required to discontinue all other centrally active medication, other 
than cholinesterase inhibitors, including psychotropic drugs, or other centrally active medications 
[e.g., CNS- penetrant beta blockers], and moderate to strong inhibitors or inducers of CYP3A4, 
CYP2D6, or other cytochromes) at least 14 days prior to the first dose of study drug (Treatment 
Period 1, Day 1) and during the study (Follow-Up Visit). For specific medications, refer to 
Subject Exclusion Criteria, Exclusions # 15 and #16. 
Benadryl (diphenhydramine) and other sedating antihistamines are permitted only at bedtime for 
night time sleep management. Hypnotics for sleep, including benzodiazepines, non-
benzodiazapines (Ambien, Lunesta), antihistamines, hydroxyzine and trazadone are permitted. 


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Other medications that are often used for sleep such as mirtazapine and quetiapine are not 
permitted.  
Other prescription or non-prescription drugs such as antihypertensive or cholesterol lowering 
drugs are allowed, if, in the Investigator’s judgement, they would not interfere with the study 
medication or the cognitive testing.  
Subjects using over-the-counter herbal preparations, dietary supplements, or nutraceuticals 
including vitamins, minerals and calcium supplements at screening may continue with these 
treatments, but must not change dosages during the study.  NSAIDs and acetaminophen are 
permissible. 
7.8 Dietary Guidelines 
There are no dietary restrictions. Subjects should follow their usual eating behaviors. 
7.9 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. 
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 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 Physical Examination (Full and Abbreviated) 
The full physical examination will be conducting at the Screening and Week 13 (or Early 
Termination) Visits as specified in the Schedule of Assessments and will include: 
• General appearance 
• Skin 
• Eyes, ears, nose, and throat (EENT) 
• Head/neck 


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• Extremities 
• Musculoskeletal examination 
• Respiratory examination 
• Cardiovascular assessment including rhythm and presence of cardiac abnormalities 
• Abdominal examination 
• Neurologic examination to record the presence of abnormalities in mental status, motor, 
and sensory function, and 
• Any additional assessments necessary to establish baseline status or evaluate symptoms 
or adverse experiences 
An abbreviated physical examination will be conducted at on Day 1 (Baseline) and Week 14 
Follow-Up and will include: 
• General appearance 
• Skin 
• Extremities 
• Respiratory examination 
• Cardiovascular assessment including rhythm and presence of cardiac abnormalities 
• Abdominal examination 
Significant findings prior to the start of dosing will be recorded on the Medical History page of 
the eCRF.  Only changes from baseline physical examination findings that meet the definition of 
a treatment-emergent AE will be recorded as an AE; any changes occurring between Screening 
and Baseline require an update to medical history. 
8.5 Height, Weight, Body Mass Index  
Body weight and height are to be measured at Screening, and body weight will be repeated at 
Baseline and the Week 13 visit 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.   
8.6 Vital Signs 
Vital signs (pulse rate, blood pressure, respiration rate, and temperature) will be measured at 
Screening, during the Treatment Visits, and Follow-Up 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.  Blood pressure at the Screening Visit 
should be obtained in both arms and the arm with the higher value should be used for ongoing 
monitoring throughout the rest of the study.  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. 
For purposes of qualifying any given subject for study participation based on 
Inclusion/Exclusion Criteria, out-of-range results may be repeated once at Screening and once at 


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Baseline. Eligibility must be confirmed at Baseline. Additional vital signs measurements may be 
performed as deemed medically necessary by the Investigator. 
8.7 Electrocardiograms 
Single 12-lead ECGs will be performed at every clinic visit except the Week 14 Follow-up Visit, 
as Visit 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, and electronic tracings 
will also be sent to a central reader for review. All ECG traces will be kept as source data. 
For purposes of qualifying any given subject for study participation based on 
Inclusion/Exclusion Criteria, the ECG may be repeated once in the case of clinically significant 
out-of-range results. The ECG may be repeated immediately or later within the visit. 
8.8 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, hematology and lipid testing and urine samples will be collected in 
accordance with acceptable laboratory procedures.  Blood samples for chemistry, hematology 
and lipid testing  performed on Day 1 and Week 13 require an 8 hour fast and will include 
glucose testing; samples obtained at all other visits do not require fasting and will not include 
glucose or lipid testing.  
A central laboratory will be used to analyze the clinical laboratory samples. 
8.9 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 reported as AEs, and followed and evaluated with additional tests if 
necessary until determination of the underlying cause or adverse event resolution. 
8.10 Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a prospective assessment instrument 
that directly classifies suicidal ideation and behavior into 11 preferred categories.8  The C-SSRS 
involves a series of probing questions to inquire about possible suicidal thinking and behavior. 


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The C-SSRS will be conducted Screening, Baseline, Week 1 and Week 4, as specified in the 
Schedule of Assessments. 
At Screening, a subject is ineligible for the study if the subject scores a suicidal ideation intensity 
of 3 or higher (per the C-SSRS) or has exhibited any suicidal behavior within the past three 
months. 
If a subject scores an intensity of 3 or higher for suicidal ideation (per the C-SSRS) during the 
Treatment and Follow-Up Visits a suicide risk assessment must be completed by the investigator.  
If a subject scores an intensity of 3 or higher for suicidal ideation and has any suicidal behavior, 
the subject will be discontinued from the study and referred for psychiatric evaluation. 
8.11 Additional Safety Measures 
Subjects and caregivers will be instructed to inform the study physician and/or research 
personnel of any AEs 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.   
8.12 Cognitive Battery 
At Screening, the Repeatable Battery for the Assessment of Neurological Status-Delayed 
Memory Index (RBANS DMI), Mini Mental State Exam (MMSE), Clinical Dementia Rating 
(CDR), and the Modified Hachinski Ischemia Scale (MHIS) will be used to assess the cognitive 
status of the subject. 
 
During the Baseline Visit, the subjects will be reassessed on RBANS and MMSE. Caregivers 
will also complete the Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Inventory (ADCS-ADL). 
 
The subjects will be assessed with the RBANS and MMSE instruments at Weeks 1, 2, 4, 8, and 
13 during the treatment period. The investigator will also assess subjects using the CGI-I scale at 
Weeks 1, 2, 4, 8, and 13.  Caregivers will be asked to complete the ADCS-ADL at Weeks 8 and 
13. 
 
Section 16.3 Cognitive Test Scales provides a summary description for each of the test in the 
cognitive battery to be assessed in this study. 
8.13 Clinical Global Impression- Improvement 
At the clinic visits during Weeks 1, 2, 4, 8, and 13, the Investigator will assess the degree of 
improvement in the subject with respect to their AD on a 1-7 point scale, where:  


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• 1=Very much improved 
• 2= Much Improved 
• 3= Minimally improved 
• 4= No Change 
• 5=Minimally worse 
• 6= Much worse 
• 7=Very much worse 
 
8.14 Pharmacokinetic Assessment 
8.14.1 Plasma Pharmacokinetic Samples 
Blood samples for BPN14770 concentrations will be drawn during the clinic visits at Weeks 1, 4, 
8 and 13.  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 × 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. 
8.14.2.1 Pharmacokinetic Sampling 
Blood samples will be centrifuged at approximately 3000 rpm for 10 minutes at 4°C. If a chilled 
centrifuge is not available, it is acceptable to keep sample on wet ice prior to centrifugation and 
use an ambient centrifuge to process the sample.  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 -70°C within 60 minutes of the blood draw.  If a clinical 
site does not have a -70°C or -80°C freezer, it is acceptable to use a -20°C freezer, but samples 
stored must be shipped for storage with the laboratory vendor within 2 weeks of collection. 
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 central laboratory for storage 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. 


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All frozen pharmacokinetic samples will be shipped with accompanying documentation (Study 
ID BPN14770-CNS-201 / 38019XX045; Site Number: XXX) to: 
Eurofins Central Laboratory Lancaster  
 Eurofins Central Laboratory, LLC.  
 2430 New Holland Pike  
 Building D, Suite 100  
Lancaster PA 17601  
United States of America 
Tel: +1 717 556 3886 
 
The central lab will ship the PK samples to the analytical lab (CMIC, Inc., Hoffman Estates, IL) 
at mutually agreed upon time points during the study. PK samples will be stored in a freezer at -
80°C both the central and analytical lab. 
 
8.14.2.2 Metabolite Sampling at Week 13 (select sites) 
At approximately 5-6 study sites, an additional sample of plasma spun for PK analysis will be 
aliquoted for assessment of BPN14770 metabolites at Week 13. Instructions for storing and 
shipping the plasma vials for metabolite assessment will be provided to the select participating 
sites. 
8.14.3 Analytical Methods 
Plasma samples for standard PK and metabolites will be analyzed for BPN14770 using  validated 
assays. 
 
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 concentration levels will be presented in tabular form by dose level and week, 
and a listing of all subjects’ data will be provided. Metabolite data will be analyzed and reported 
separately from the clinical study data. 
8.15 Biomarker Assessments 
Blood samples for future biomarker assessments will be drawn during the clinic visits at Baseline 
and Weeks 1, 4, 8 and 13.  Samples will be drawn at the time of the clinic visit, with 
documentation of the date and time the samples were obtained.  
Blood samples will be collected in Vacutainer tubes (2 x 4 mL) containing K2 EDTA as a 
preservative.  Blood samples will be kept on wet ice from the time of collection and throughout 
processing until frozen. 
One tube will be centrifuged at approximately 3000 rpm for 10 minutes at 4°C. If a chilled 
centrifuge is not available, it is acceptable to keep sample on wet ice prior to centrifugation and 
use an ambient centrifuge to process the sample.    The resulting plasma sample will be harvested 


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and transferred evenly into two appropriately labeled polypropylene screw-cap tubes.  The other 
tube will be retained as whole blood. The plasma and whole blood tubes for biomarker use will 
be placed in a freezer at -70°C within 60 minutes of the blood draw. If a clinical site does not 
have a -70°C or -80°C freezer, it is acceptable to use a -20°C freezer, but samples stored must be 
shipped for storage  with the laboratory vendor within 2 weeks of collection. These biomarker 
samples will be retained and may be utilized subsequently for biomarker assessment.   
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 eCRF. 
Adverse events, which include abnormal and clinically significant clinical laboratory test 
variables, will be monitored and documented from the time Informed Consent 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 present prior to 
consent should be recorded in medical history. Beginning with the signing of the informed 
consent until the time of the first dose of study drug, investigators should make updates to source 
records to document any pre-existing medical condition or signs or symptoms that change in 
severity, frequency, or seriousness in the medical history; if the subject is subsequently 
randomized, these occurrences will be reported as adverse events that began prior to dosing. 
Serious adverse events that occur prior to the first dose of study drug should be reported 
similarly, except that an SAE report will be completed regardless of whether the subject is 
randomized..  
Beginning with the first dose of study drug, investigators should make an assessment for adverse 
events at each visit and record all adverse events, non-serious and serious, on the appropriate 
adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. 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 eCRF. 
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 eCRF.  
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, 


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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: 
• Death; 
• A life-threatening adverse event; 
• 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. 
• 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.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• 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 


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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. 
• 
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. 


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• 
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 non-serious AEs that are ongoing at study completion or study withdrawal 
must be followed until resolution of the AEs or for 30 days after the last dose of study drug, 
whichever comes first.  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. 
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 and clinical research organization 
(CRO) within 24 hours after the SAE detection, observation, or report of occurrence (regardless 
of the relationship to study treatment).  The Sponsor and the CRO medical monitor contact 
information for SAE reporting is provided below.  
 
Tetra Discovery Partners, Inc. 
Email: 
 
Office: 
 
24-hour contact number (cell): 
 


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and 
 
Syneos Health 
Email: 
 
24-hour contact number (cell): 
 
 
The final SAE report must contain the following information, but the event may be initially 
reported without complete data, if necessary: 
 
Study name/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). 
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. 
9.4  Data Safety and Monitoring Committee 
An independent data and safety monitoring board (DSMB) will provide safety oversight for this 
study.  The DSMB will consist of two qualified MDs and one statistician.  The DSMB will 
review standard safety data approximately every four (4) months, based on enrollment rate.  A 


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DSMB charter will be developed to further outline the DSMB responsibilities and the desired 
listings, summaries and analyses.  
9.5 Reports of Pregnancy 
If a subject or partner of a subject participating in the study becomes pregnant during the study 
or within 30 days of discontinuing study drug, the Investigator should report the pregnancy to the 
Sponsor within 24 hours of being notified. Investigator will complete then forward the Exposure 
In Utero form to the Sponsor.   
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed.  
The subject should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify the 
Sponsor. At the completion of the pregnancy, the Investigator will document the outcome of the 
pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as an 
SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
10 STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
10.1 Schedule of Assessments 
The study timetable in the Schedule of Assessments 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, unless additional time is required 
for washout of concomitant medications. 
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:  
• Obtain informed consent; 
• Obtain medical/surgical history; 
• Obtain demographics and social history (tobacco, alcohol, and/or drug use); 
• Obtain prior/concomitant medication use; 
• Obtain vital signs; 
• Obtain height and weight; 
• Conduct full physical exam; 
• Conduct single ECG; 
• Serology (HbsAg, HCV) 
• Serum pregnancy (females of childbearing potential , even if using birth control) 
• Draw blood samples for Chemistry and Hematology (fasting or nonfasting);  
• Collect urine for safety urinalysis; 
• ApoE4 testing, if not in medical history;  


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• Conduct C-SSRS assessment; 
• Conduct RBANS, MMSE, CDR and MHIS evaluations 
• Evaluate inclusion and exclusion criteria. 
10.3 Baseline (Day 1) 
Subjects will return to the clinic for the Baseline Visit following successful screening.   
Prior to Randomization  
The following assessments will be completed:  
• Complete urine pregnancy test (females of childbearing potential , even if using birth 
control) 
• Conduct abbreviated physical exam; 
• Obtain vital signs; 
• Obtain weight; 
• Draw blood samples for Chemistry, Hematology and Lipids (following a minimum 8-
hour fast);  
• Draw blood sample for biomarkers (no PK sample drawn); 
• Collect urine for safety urinalysis;   
• Conduct ECG (single); 
• Conduct C-SSRS assessment; 
• Conduct RBANS and MMSE evaluations; 
• Conduct ADCS-ADL assessment; 
• Record any updates to medical/surgical history; 
• Record any updates to prior/concomitant medication use; 
• Assess and record and adverse events;  
• Re-evaluate inclusion and exclusion criteria based on preceding activities; and 
• Verify continued eligibility. 
 
If subject remains eligible for the study: 
• Randomize subject; 
• Dispense study medication 
10.4 Week 1 (Day 7 ± 2) 
The following assessments will be completed at the Week 1 visit: 
• Collect vital signs; 
• Conduct ECG (single); 
• Draw blood samples for Chemistry and Hematology (fasting or nonfasting); 
• Draw blood samples for pharmacokinetic analysis and biomarkers; 
• Collect urine for safety urinalysis; 
• Conduct C-SSRS assessment; 
• Conduct RBANS, MMSE, and CGI-I evaluations; 
• Record  pill count remaining in bottle to assess dosing compliance;  


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• Record any updates to concomitant medication use; and 
• Assess and record and adverse events. 
 
10.5 Week 2 (Day 14 ± 2) 
The following assessments will be completed at the Week 2 visit: 
• Collect vital signs; 
• Conduct ECG (single); 
• Draw blood samples for Chemistry and Hematology (fasting or nonfasting); 
• Conduct RBANS and MMSE evaluations; 
• Assess CGI-I; 
• Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance; 
• Dispense study medication; 
• Record any updates to concomitant medication use; and 
• Assess and record and adverse events. 
10.6 Week 4 (Day 28 ± 2) 
The following assessments will be completed at the Week 4 visit: 
• Collect vital signs; 
• Conduct ECG (single); 
• Draw blood samples for Chemistry and Hematology (fasting or nonfasting); 
• Draw blood samples for pharmacokinetic analysis and biomarkers; 
• Collect urine for safety urinalysis; 
• Conduct C-SSRS assessment; 
• Conduct RBANS and MMSE evaluations; 
• Assess CGI-I; 
• Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance; 
• Dispense study medication; 
• Record any updates to concomitant medication use; and 
• Assess and record and adverse events. 
10.7 Week 8 (Day 56 ± 3) 
The following assessments will be completed at the Week 8 visit: 
• Collect vital signs; 
• Conduct ECG (single); 
• Draw blood samples for Chemistry and Hematology (fasting or nonfasting); 
• Draw blood samples for pharmacokinetic analysis and biomarkers; 
• Conduct RBANS and MMSE evaluations; 
• Conduct ADCS-ADL assessment; 


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• Assess CGI-I; 
• Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance; 
• Dispense study medication; 
• Record any updates to concomitant medication use; and 
• Assess and record and adverse events. 
10.8 Week 13 (Day 91 ± 3) 
The following assessments will be completed at the Week 13 visit: 
• Conduct full physical exam; 
• Collect weight; 
• Collect vital signs; 
• Conduct ECG (single); 
• Draw blood samples for: 
o Chemistry, Hematology and Lipids (following a minimum 8-hour fast); 
o Pharmacokinetic analysis and biomarkers; 
o Serum pregnancy test (females of childbearing potential , even if using birth 
control); 
• Collect urine for safety urinalysis; 
• Conduct RBANS, MMSE and CDR evaluations; 
• Conduct ADCS-ADL assessment; 
• Assess CGI-I; 
• Conduct C-SSRS assessment; 
• Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance; 
• Record any updates to concomitant medication use; and 
• Assess and record and adverse events. 
 
10.9 Week 14 Follow-up Visit (Day 98 ± 3) 
The following assessments will be completed at the final follow up visit at Week 14: 
• Obtain vital signs;  
• Conduct abbreviated physical exam; 
• Assess and record AEs; 
• Record any updates to concomitant medication use; and 
• Record final subject disposition. 
 
10.10 Early Termination 
It is hoped that all subjects can be followed through to the conclusion of the study at Week 14.  
However, if an early termination occurs, the Week 13 procedures should be completed at the 
time of the subject’s withdrawal (if possible) and an explanation provided as to why the subject 


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is withdrawing or being withdrawn from the study.  Procedures to be completed early 
termination: 
• Conduct a full physical exam;  
• Collect weight; 
• Collect vital signs; 
• Conduct ECG (single); 
• Draw blood samples for: 
o Chemistry, Hematology and Lipids (following a minimum 8-hour fast); 
o Pharmacokinetic analysis; 
o Serum pregnancy test (females of childbearing potential, even if using birth 
control); 
• Collect urine for safety urinalysis; 
• Conduct RBANS, MMSE, and CDR evaluations; 
• Conduct ADCS-ADL assessment; 
• Conduct C-SSRS assessment; 
• Collect study medication and record  pill count remaining in bottle to assess dosing 
compliance; 
• Record any updates to concomitant medication use; 
• Assess and record and adverse events; and 
• Record final subject disposition. 
 
11 PLANNED STATISTICAL METHODS 
11.1 Sample Size 
The BPN14770-CNS-201 study will enroll 255 subjects (85 per treatment arm), in anticipation of 
evaluating at least 240 subjects (80 per treatment).   The Primary Efficacy Outcome measure will 
be change from baseline at Week 13 for the Repeatable Battery for the Assessment of 
Neurological Status - Delayed Memory Index (RBANS DMI).   
 
The normalized mean of the RBANS DMI is 100, with an SD of 15, and the test-retest reliability 
is 0.80 with no practice effects using alternate versions of the test.9   RBANS DMI was used in a 
recent natural history study of Mild Cognitive Impairment (MCI) due to probable AD.16 In the 
large amnestic MCI sample (81 subjects), the mean was 73.4 with a SD of 16.5 in a normal 
distribution.  Performance of healthy, age-matched controls was a mean of 101.4 with a SD of 
14.4 (81 subjects) yielding estimates of the standard deviation for the DMI from 14.4-16.5.    
Therefore, the power analysis is based on the assumption that the standard deviation of the 
response variable is 16.   
 
The power of the proposed study is driven by the assumed difference between BPN14770 25mg 
(higher dose) and placebo.  Based on randomization of 80 patients per group into the parallel-
design study, the probability is 80 percent that the study will detect a treatment difference at a 
two-sided 0.05 significance level, if the true difference between BPN14770 25 mg and placebo is 


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7.15 units. Using the standardized mean difference (SMD) to estimate effect size,17 a change of 
7.15 units on the DMI score is an effect size of 0.45. 
   
Table 1 provides sample size estimates for 80 percent and 90 percent probability that the study 
will detect a treatment difference at a two-sided 0.05 significance level assuming the standard 
deviation of the DMI is 16. 
 
Table 1 Clinical Sample Size (1:1 Active + Placebo) Based on Effect Size (Change From Baseline) And Desired 
Power 
 
Number of Subjects Per Group Based on Desired Effect Size (SMD) 
Standardized Mean Difference (SMD) 
0.3 
0.35 
0.4 
0.45 
0.5 
0.75 
RBANS DMI change (M1-M2) 
4.8 
5.6 
6.4 
7.2 
8 
12 
Number of Subjects (Power 0.8) 
176 
130 
100 
79 
64 
29 
Number of Subjects (Power 0.9) 
235 
173 
133 
105 
86 
39 
  
For comparison, a donepezil study reported by Seltzer et al., 2004, randomized a total of 153 
subjects (2:1 active vs placebo) and reported treatment benefit at a significance level of 0.03 after 
12 weeks of treatment. 18   In a larger study of mild-to-moderate AD patients, the effect size of 
donepezil reported by Rogers et al. 1998 was 0.4,19 so the assumption of an effect size of 0.45  
for BPN14770 in a milder, early AD population, using a sensitive outcome measure, is 
reasonable.   
 
Therefore, based on clinical trials of donepezil in a similar population, the proposed sample size 
will provide adequate power to detect a clinically and statistically significant difference of 
BPN14770 treatment in early AD. 
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 per protocol (PP) population (randomized subjects who received at 
least one dose of treatment and returned for at least one follow-up visit with no significant 
protocol violations) and the completers (CP) population (randomized subjects who completed all 
13 weeks of treatment 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. 


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11.4 Efficacy: Cognitive Testing Analysis 
Change from baseline will be calculated for the primary and secondary efficacy parameters at 
each time point and descriptive statistics provided for each time point. Summary plots of these 
data will also be provided. For RBANS DMI and total score, MMSE score, and ADCS-ADL 
total score, pairwise differences in change from baseline between the treatment groups (10 mg vs 
25 mg BPN14770, 10 mg BPN14770 vs Placebo, 25 mg BPN14770 vs Placebo) will be assessed 
using an analysis of covariance (ANCOVA) model that includes baseline as a covariate and 
factors for week, site and treatment and the interaction term for week and treatment ; the 
pairwise differences will be assessed at each time point.  CDR sum of boxes will be analyzed in 
the same manner.  
Change from baseline in the other RBANS index scores (immediate memory, 
visuospatial/constructional, attention, language) will be summarized by time point, with 
descriptive statistics provided. 
The composite endpoint will be based on the AD Composite Score (ADCOMS), a composite 
clinical outcome for prodromal Alzheimer's disease trials.20 The composite endpoint and analysis 
model will be fully specified in the statistical analysis plan. 
The efficacy analyses will be performed on the ITT, PP and CP analysis populations. 
Supplemental analyses assessing treatment effect relative to severity of disease based on baseline 
MMSE score may also be performed. 
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.  All AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by treatment group and for the combined BPN14770 groups using 
preferred term and primary system organ class.  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, C-SSRS, 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. 
For each AE, the difference in incidence rates between each BPN14770 dose group will be 
compared to the placebo group using a Fisher’s exact test.   
11.6 Pharmacokinetic Analysis 
BPN14770 plasma levels will be presented in tabular form by study arm, dose level and subject. 


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12 DATA MANAGEMENT 
12.1 Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. 
The CRAs 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. An eCRF 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 
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 Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA for medical history and adverse events, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
12.5 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 eCRFs must be reviewed and electronically 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 


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Page 51 of 61 
§ 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. 
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 SAEs or other safety information 
reported by the clinical site or the Sponsor. 
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.  


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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 (or legally acceptable representative) adequate opportunity to read the written informed 
consent and ask any questions. The Investigator will obtain written informed consent from each 
subject (or legally acceptable representative) before any study-specific activity is performed and 
should document in the source documentation that consent was obtained prior to any study-
specific activity. If consent is signed by a legally authorized representative, the subject must 
provide verbal assent, which will be documented on the consent form. 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, eCRFs and procedures for their completion, informed consent process, management of 
investigational product, and the procedure for reporting adverse events such as SAEs. 
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 eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF 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 


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Page 53 of 61 
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. 
13.6 Record Storage and Retention 
Records of subjects, source documents, monitoring visit logs, eCRFs, 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. 
 
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., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, 
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. 


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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 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. 
 
14 ADMINISTRATIVE INFORMATION 
14.1 Sponsor  
Tetra Discovery Partners, Inc. 
301 Michigan Ave NE 
Grand Rapids, MI 49503-3314 
Phone: 
 
 
 
14.2 Clinical Research Organization 
Syneos Health  
1030 Sync Street  
Morrisville, NC 27560 
Phone: 919. 876.9300


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Page 55 of 61 
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 Good Clinical Practice Guideline. 
3. Gurney ME, D'Amato EC, Burgin AB.  Phosphodiesterase-4 (PDE4) molecular 
pharmacology and Alzheimer's disease.  Neurotherapeutics: the journal of the American 
Society for Experimental NeuroTherapeutics 2015; 12:49-56. 
4. Bennett DA, Yu L, De Jager PL.  Building a pipeline to discover and validate novel 
therapeutic targets and lead compounds for Alzheimer's disease.  Biochem Pharmacol 
2014; 88:617-30. 
5. 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. 
6. Fox D, 3rd, Burgin AB, Gurney ME.  Structural basis for the design of selective 
phosphodiesterase 4B inhibitors.  Cellular signaling 2014; 26:657-63. 
7. Zhang C, Xu Y, Gurney M, Role of Phosphodiesterase 4D in Memory and Cognition. 
2016 Gordon Research Conference Poster Presentation. 
8. Posner, K, GK Brown, B Stanley et al., 2011, The Columbia-Suicide Severity Rating 
Scale (C448 SSRS): Internal Validity and Internal Consistency Findings From Three 
Multi-Site Studies With 449 Adolescents and Adults, Am J Psychiatry, 168:1266-1277. 
9. Randolph C., Tierney M. C., Mohr E., Chase T. N. The Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS): Preliminary clinical 
validity. Journal of Clinical and Experimental Neuropsychology. 1998;20(3):310–
319. doi:10.1076/jcen.20.3.310.823. [PubMed] 
10. Spering CC, et al. Diagnostic Accuracy of the MMSE in Detecting Probable and Possible 
Alzheimer’s Disease in Ethnically Diverse Highly Educated Individuals: An Analysis of 
the NACC Database.J Gerontol A Biol Sci Med Sci. 2012Augl 67(8):890-896. 
Doi:19.1093/Gerona/gls006. 
11. Galasko D, Bennett D, Sano M et al. An inventory to assess activities of daily living for 
clinical trials in Alzheimer’s disease. The Alzheimer’s disease cooperative study. 
Alzheimer Dis Assoc Disord 1997; 11 (Suppl. 2): 33–9. 
12. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology. 1993 Nov;43(11):2412-4. 
13. Morris, J. (1997). Clinical Dementia Rating: A Reliable and Valid Diagnostic and 
Staging Measure for Dementia of the Alzheimer Type. International 
Psychogeriatrics, 9(S1), 173-176. doi:10.1017/S1041610297004870 
14. Fischer P, Jellinger K, Gatterer G, Danielczyk W. Prospective neuropathological 
validation of Hachinski’s Ischaemic Score on dementias. Journal of Neorology, 
Neurosurgery and  Psychiatry 1991; 54:580-583. 
15. Loeb C and Gandolfo C. Diagnostic Evaluation of Degenerative and Vascular Dementia. 
Stroke 1983; 14(3): 399-401. doi: 10.1161/01.STR.14.3.399 
16. Karantzoulis, S., Novitski, J., Gold, M. & Randolph, C. The Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS): Utility in detection and 
characterization of mild cognitive impairment due to Alzheimer's disease. Arch Clin 
Neuropsychol 28, 837-844 (2013). 


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17. Faraone, S.V. Interpreting estimates of treatment effects: implications for managed care. 
P T 33, 700-711 (2008). 
18. Seltzer, B., et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized 
placebo-controlled trial. Arch Neurol 61, 1852-1856 (2004). 
19. Rogers, S.L., Farlow, M.R., Doody, R.S., Mohs, R. & Friedhoff, L.T. A 24-week, 
double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. 
Donepezil Study Group. Neurology 50, 136-145 (1998). 
20. Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for 
prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016;87(9):993–
999. doi:10.1136/jnnp-2015-312383. 
 


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16 APPENDICES 
16.1 Schedule of Assessments 
 
Screening 
Baseline 
Treatment 
Follow-Up 
 
Days -28 
thru Day 0 
Day 1 
Week 1 
Week 2 
Week 4 
Week 8 
Week 13e 
Week 14 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Target Study Day 
--- 
1 
7 
14 
28 
56 
91 
98 
Visit Window 
 
 
±2 
±2 
±2 
±3 
±3 
±3 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Criteria Confirmed 
X 
X  
 
 
 
 
 
 
Medical/Surgical History 
X 
X 
 
 
 
 
 
 
Demographics and Social 
History 
X 
 
 
 
 
 
 
 
Full Physical Exam  
X  
 
 
 
 
 
X 
 
Abbreviated Physical Exam 
 
X 
 
 
 
 
 
X 
Height, Weight, BMI 
X 
Xa 
 
 
 
 
Xa 
 
Vital Signs b 
X 
X 
X 
X 
X 
X 
X 
X 
ECGs (single)   
X 
X 
X 
X 
X 
X 
X 
 
Serology (HbsAg, HCV) 
X 
 
 
 
 
 
 
 
Chemistry and Hematology 
X 
Xc 
X 
X 
X 
X 
Xc 
 
Lipids 
 
Xc 
 
 
 
 
Xc 
 
ApoE4 testing 
X 
 
 
 
 
 
 
 
Serum Pregnancy d 
X 
 
 
 
 
 
X 
 
Urine Pregnancy d 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
C-SSRS 
X 
X  
X 
 
X 
 
X 
 
RBANS 
X 
X 
X 
X 
X 
X 
X 
 
MMSE 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
 
   
 
X 
X 
 
CDR 
X 
 
 
 
 
 
X 
 
Hachinski (MHIS-NACC) 
X 
 
 
 
 
 
 
 
PK and Biomarker Sampling 
 
X 
(biomarkers 
only) 
X 
 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
Dispense Medication 
 
X 
 
X 
X 
X 
 
 
First Dose of Medication 
 
X 
(PM dose 
following 
dinner) 
 
 
 
 
 
 
Daily Medication 
Administration BID 
 
 
X-------------------------------------------------------------X 
 
Medication accountability 
 
 
X 
X 
X 
X 
X 
 
Prior/Concomitant Medication 
Recording 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 


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Final Disposition 
 
 
 
 
 
 
 
X 
a   Weight only  
b  Vital signs include pulse rate, blood pressure, respiration rate, and temperature  
c  Fasting for a minimum of 8 hours prior to blood draw is required at Baseline (Day 1) and End of Treatment (Week 13)  
d  All females of childbearing potential, even if using birth control)  
e If a subject terminates from the study prior to Week 13, evaluations intended for Week 13 should be completed at discontinuation, if possible. 


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16.2 Clinical Laboratory Analytes 
 
Standard Chemistry  
Alanine aminotransferase (ALT)  
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase (AST) 
Bicarbonate  
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Glucosea 
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) 
 
Lipidsb 
High Density Lipoprotein (HDL) 
Low Density Lipoprotein (LDL) 
Total Cholesterol 
 
 
Urinalysisc 
Bilirubin 
Blood 
Glucose 
Ketones 
Nitrite 
pH 
Protein 
Specific Gravity 
Urobilinogen  
Leukocyte esterase 
a  Glucose will only be tested in fasting blood samples obtained at Baseline (Day 1) and End of Treatment (Week 13 or early 
termination) 
b  Lipids will only be tested in fasting blood samples obtained at Baseline (Day 1) and End of Treatment (Week 13 or early 
termination) 
c  If protein, urine occult blood, nitrite, or leukocyte esterase values are out of range, the microscopic examination will be 
reported.  
 
Pregnancy Test  
Serum pregnancy test at Screening and urine pregnancy tests at each Day-1 Treatment Visit will be 
administered to all females of childbearing potential, even if using birth control. 
Serology 
Hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) 


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16.3 Cognitive Test Scales  
16.3.1 RBANS 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, 
individually administered test measuring attention, language, visuospatial/constructional abilities, 
and immediate and delayed memory.9 It consists of 12 subtests, which yield five Index scores and 
a Total Scale score. 
16.3.2 MMSE 
The Mini–Mental State Examination (MMSE) is a 30-point questionnaire that is used extensively 
in clinical and research settings to measure cognitive impairment. It is commonly used to screen 
for dementia.10 It consists of a series of questions and tests, each of which scores points if 
answered correctly. The MMSE tests a number of different mental abilities, including a person's 
memory, attention and language. 
16.3.3 ADCS-ADL 
The Alzheimer’s Disease Cooperative Study scale for ADL (ADCS- ADL)10,11  is administered by 
an independent rater. The interview was developed to assess impairment of everyday tasks in non-
demented individuals with high sensitivity.  
16.3.4 CDR 
The Washington University Clinical Dementia Rating scale12,13 is a structured, clinician-rated 
interview that collects information on cognitive capacity from both the collateral source and 
patient for the evaluation of staging severity of dementia. The CDR was developed primarily to 
assess severity level in persons with dementia but it can be used to stage dementia in other 
illnesses as well (e.g., Parkinson's disease). Six domains are assessed and then synthesized to 
assign a Global CDR score. The domains are memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care. Impairment is defined only when caused 
by cognitive loss rather than by physical disability or other non-cognitive factors. Severity ratings 
range along a 5-point scale (except for the personal care domain): 
• CDR-0: no cognitive impairment 
• CDR-0.5: questionable or very mild dementia 
• CDR-1: mild 
• CDR-2: moderate 
• CDR-3: severe 
 
The CDR is frequently utilized in clinical and research settings to describe stage-dependent 
features of dementia and for use as a clinically-meaningful outcome measure in clinical drug trials.  
 
16.3.5 Modified Hachinski Ischemia Score (MHIS) 
A modified version of the Ischemic Score of Hachinski uses 4 items of Hachinski's Ischemic Score 
plus CT findings (if available in subject’s history) as a suitable tool for the diagnosis of vascular 


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dementia.14,15 Such a modified ischemic score could comprise 5 items, that is, 4 relevant items of 
Ischemic Score and the CT features (if available). 
1. Abrupt onset (2 points) 
2. History of stroke (1 point) 
3. Focal neurological symptoms  (2 points) 
4. Focal neurological signs  (2 points) 
5. CT-Low density areas isolated (2 points) or  multiple  (3 points) 
 Maximum Total Score = 10 
A 9-10 point total score points to the existence of old or recent cerebrovascular lesions, simple or 
multiple. 
 

SAP_003.pdf: 
This document is confidential. 
SAP Version: Final V3.0, 02-Mar-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 1 of 46 
Statistical Analysis Plan 
Sponsor Name: Tetra Discovery Partners, Inc. 
Protocol Number: BPN14770-CNS-201 
Protocol Title: A Randomized, Double-blind, Placebo-controlled, 3-Arm Parallel Design Study to 
Evaluate the Effects of BPN14770 in Patients with Early Stage Alzheimer’s Disease 
Protocol Version and Date: Amendment 3.0, 24 September 2019 
Syneos Health Project Code: 7001704 
Author: 
, Biostatistician 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Tetra Discovery Partners, Inc. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Tetra Discovery 
Partners, Inc. However, this document may be disclosed to appropriate Institutional Review Board and 
Ethics Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected breach of 
this obligation, Syneos Health should be notified promptly. 
NCT03817684


Statistical Analysis Plan  
Sponsor: Tetra Discovery Partners, Inc.; Protocol No.: BPN14770-CNS-201 
 
This document is confidential. 
SAP Version: Final V3.0, 02-Mar-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 2 of 46 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
0.1 
07-May-2019
 
Initial Release Version 
0.2 
01-Nov-2019
 
Updated per Tetra review comments on first draft SAP 
1.0 
09-Dec-2019
 
Updated per Tetra review comments on second draft 
SAP 
1.1 
14-Jan-2020
 
Add section 8.3 Multiple Testing Strategy 
2.0 
16-Jan-2020
 
Updated per Tetra review comments and modified 
analysis for CGI-I 
3.0 
02-Mar-2020
 
A number of clarifications were made to the text to ensure 
clarity of methods. 
Updated primary analysis to accommodate the study 
design and the repeated measures collected for each 
endpoint.  Added detail regarding each efficacy endpoint, 
eg, what the scale is for each endpoint, interpretation (eg, 
are lower values ‘better’ or ‘worse’), how missing 
individual questions/items for each scale affect derivation 
of the total and/or domain scores.   
For safety, additional specification was added on 
assessment of laboratory shifts (low/normal/high) as well 
as ECG assessment of QTc. 
Patient 
 was the same 
subject, randomized at 3 different treatment centers.  Due 
to the multiple treatments and overlapping treatment 
periods, this patient (and all 3 patient numbers associated 
with the patient) is excluded from the Safety, mITT, PP, 
Completers, and PK populations.  This patient will be 
reported in the CSR via a detailed patient narrative. 




Statistical Analysis Plan  
Sponsor: Tetra Discovery Partners, Inc.; Protocol No.: BPN14770-CNS-201 
 
 
This document is confidential. 
SAP Version: Final V3.0, 02-Mar-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 4 of 46 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
 
Glossary of Abbreviations ................................................................................................... 7 
 
Purpose .............................................................................................................................. 9 
 
Study Introduction ............................................................................................................ 10 
 
Endpoints ......................................................................................................................... 15 
 
Analysis Populations ........................................................................................................ 16 
 
General Aspects for Statistical Analysis ........................................................................... 18 


Statistical Analysis Plan  
Sponsor: Tetra Discovery Partners, Inc.; Protocol No.: BPN14770-CNS-201 
 
 
This document is confidential. 
SAP Version: Final V3.0, 02-Mar-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 5 of 46 
 
Demographic, Other Baseline Characteristics and Medication ......................................... 20 
 
Efficacy ............................................................................................................................ 23 
 
Analysis Of Pharmacokinetics .......................................................................................... 32 
 
Analysis Of Biomarker Data.............................................................................................. 33 
 
Safety ............................................................................................................................... 34 


Statistical Analysis Plan  
Sponsor: Tetra Discovery Partners, Inc.; Protocol No.: BPN14770-CNS-201 
 
 
This document is confidential. 
SAP Version: Final V3.0, 02-Mar-2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
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Changes from Analysis Planned in Protocol ..................................................................... 40 
 
Reference List .................................................................................................................. 41 
 
Programming Considerations ........................................................................................... 42 
 
Quality Control ................................................................................................................. 46 
 
 


Statistical Analysis Plan  
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Glossary of Abbreviations 
Abbreviation 
Description 
AD 
Alzheimer’s disease 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Inventory 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ApoE4 
Apolipoprotein E4  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating – Sum of Boxes 
CGI-I 
Clinical Global Impression – Improvement 
CI 
Confidence Interval 
CP 
Completers 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTMS 
Clinical Trial Management System 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
GLM 
Generalized Linear Models 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ITT 
Intent-to-Treat 
LSMeans 
Least Square Mean 
MMRM  
Mixed model for repeated measures 
MAR 
Missing at Random 
MNAR 
Missing Not at Random 
Max 
Maximum 
MCI 
Mild Cognitive Impairment  
MedDRA 
Medical Dictionary for Regulatory Activities 
MHIS 
Modified Hachinski Ischemia Score 
Min 
Minimum 


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Abbreviation 
Description 
MMSE 
Mini Mental State Examination 
N/A 
Not Applicable 
PP 
Per Protocol 
PT 
Preferred Term 
QTc 
Corrected QT Interval 
RBANS (DMI) 
Repeatable Battery for the Assessment of Neurological Status 
(Delayed Memory Index) 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SMD 
Standardized Mean Difference  
SOC 
System Organ Class 
SOP 
Standard operating procedure 
TEAE 
Treatment-eEmergent adverse event 
TFL 
Table, Figure, and Listing 
WHO 
World Health Organization 
 


Statistical Analysis Plan  
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Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables, and 
figures that will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures, and listings. 
 
Timings of Analyses 
The final analysis is planned after all subjects complete the final study visit or terminate early from the 
main phase of the study and the data processing has been completed to lock the study database.  Prior 
to unblinding the treatment allocations, the per-protocol population will be identified and documented. 
Unless otherwise specified, the analysis includes all data collected in the database through the time of the 
database lock.    
Note, there are no planned interim analyses in this study. 


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Study Introduction 
 
Study Objective 
In subjects with a clinical diagnosis of early stage Alzheimer’s disease (AD) receiving cholinesterase 
inhibitor therapy: 
• To evaluate the efficacy of two dose levels (10 mg bid and 25 mg bid) of BPN14770 as compared 
to placebo over a 13-week treatment period 
• To evaluate the safety and tolerability of BPN14770 10 and 25 mg bid as compared to placebo 
over a 13-week treatment period 
• To obtain pharmacokinetic data on BPN14770 in this subject population.  
The outcomes from this study will be used to determine the dose(s) to be used in subsequent Phase 3 
studies.   
 
Brief Description 
This is a Phase 2, randomized, double-blind, placebo-controlled, 3-arm, parallel-design study to evaluate 
the effects of BPN14770 in approximately 255 subjects with a clinical diagnosis of early stage AD. The 
study will consist of a Screening period of 28 days or less. The Screening period will be followed by a 13-
week double-blind treatment period, and a final follow-up visit for safety one week after treatment is 
concluded. 
Randomization will be stratified based on presence or absence of an ApoE4 allele in the subject’s genetic 
profile. Within each stratum, subjects will be randomized in a blinded, balanced fashion to receive either 
BPN14770 10mg bid, BPN14770 25 mg bid, or matching placebo. A target of 80 evaluable subjects per 
group (240 total) is planned (see the sample size determination in Section 3.4). Approximately 85 
subjects per group will be enrolled (255 total) in order to account for potential dropouts. Subjects will have 
a total of eight clinic visits: Screening; Baseline (Day 1); Weeks 1, 2, 4, 8, 13, and the final Follow-up 
Visit. The screening visit will consist of consenting the subject, obtaining a medical history, full physical 
exam, height, weight, BMI, ECG, serology and drug testing, chemistry, hematology, urinalysis, ApoE4 
testing, pregnancy testing, and cognitive assessments. If the subject fully qualifies for the study, 
randomization will occur at the Baseline visit following verification of continued eligibitly, at which time the 
subject will receive study medication. 
Cognitive testing will occur at each visit, Week 1 through Week 13, but notat the  final Follow-up Visit 
(note, not all cognitive assessments are performed at each visit). Safety assessments will also be 
performed at each visit, to include adverse event monitoring, vital signs, ECG, and chemistry and 
hematology. Urinalysis will also be performed at Screening and Baseline and Weeks 1, 4 and 13. Lipid 
testing will be performed at Baseline and Week 13. Risk of suicidality will be assessed at Screening, 
Baseline and Weeks 1, 4, and 13. 
Pharmacokinetic sampling will be performed at the clinic visits at Weeks 1, 4, 8 and 13. 
 
Subject Selection 
Individuals are eligible for the study if they meet all of the inclusion and none of the exclusion criteria. The 
inclusion/ exclusion criteria will be assessed during Screening, which will be up to 28 days prior to first 


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study drug administration. Continued subject eligibility will be verified on Baseline at Baseline, prior to 
randomization.  Specifically, subjects must meet the following AD criteria: 
• 
Clinical Dementia Rating (CDR) score of 0.5 or 1 (on a scale from 0 to 3, with higher scores 
indicating worse outcome), with Memory Box score of 0.5 or greater. 
• 
MMSE score of 20 or greater (range 0 to 30, with lower scores indicating worse outcome) 
• 
RBANS DMI score < 85 (range 40  to 160, with lower scores indicating worse outcome) 
See Sections 6.2 and 6.3 in the study protocol for the complete list of all eligibility criteria. 
 
Determination of Sample Size 
The BPN14770-CNS-201 study will enroll 255 subjects (85 per treatment arm), in anticipation of 
evaluating at least 240 subjects (80 per treatment). The Primary Efficacy Outcome measure will be 
change from baseline at Week 13 for the Repeatable Battery for the Assessment of Neurological Status - 
Delayed Memory Index (RBANS DMI). 
The normalized mean of the RBANS DMI is 100, with an SD of 15, and the test-retest reliability is 0.80 
with no practice effects using alternate versions of the test [Randolph 1998]. RBANS DMI was used in a 
recent natural history study of Mild Cognitive Impairment (MCI) due to probable AD [Karantzoulis 2013]. 
In the large amnestic MCI sample (81 subjects), the mean was 73.4 with a SD of 16.5 in a normal 
distribution. Performance of healthy, age-matched controls was a mean of 101.4 with a SD of 14.4 (81 
subjects) yielding estimates of the standard deviation for the DMI from 14.4-16.5. Therefore, the power 
analysis is based on the assumption that the standard deviation of the response variable is 16. 
The power of the proposed study is driven by the assumed difference between BPN14770 25mg (higher 
dose) and placebo. Based on randomization of 80 subjects per group into the parallel-design study, the 
probability is 80 percent that the study will detect a treatment difference at a two-sided 0.05 significance 
level, if the true difference between BPN14770 25 mg and placebo is 7.15 units. Using the standardized 
mean difference (SMD) to estimate effect size [Faraone 2008], a change of 7.15 units on the DMI score is 
an effect size of 0.45. 
Table 1 provides sample size estimates for 80 percent and 90 percent probability that the study will detect 
a treatment difference at a two-sided 0.05 significance level assuming the standard deviation of the DMI 
is 16. 
Table 1     Clinical Sample Size (1:1 Active + Placebo) Based on Effect Size (Change From Baseline) And 
Desired Power 
 
Number of Subjects Per Group Based on Desired Effect Size 
(SMD) 
Standardized Mean Difference (SMD) 
0.3 
0.35 
0.4 
0.45 
0.5 
0.75 
RBANS DMI change (M1-M2) 
4.8 
5.6 
6.4 
7.2 
8 
12 
Number of Subjects (Power 0.8) 
176 
130 
100 
79 
64 
29 
Number of Subjects (Power 0.9) 
235 
173 
133 
105 
86 
39 
For comparison, a donepezil study reported by Seltzer et al., 2004, randomized a total of 153 subjects 
(2:1 active vs placebo) and reported treatment benefit at a significance level of 0.03 after 12 weeks of 


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treatment [Seltzer 2004]. In a larger study of mild-to-moderate AD subjects, the effect size of donepezil 
reported by Rogers et al. 1998 was 0.4 [Rogers 1998],so the assumption of an effect size of 0.45 for 
BPN14770 in a milder, early AD population, using a sensitive outcome measure, is reasonable. 
Therefore, based on clinical trials of donepezil in a similar population, the proposed sample size will 
provide adequate power to detect a clinically and statistically significant difference of BPN14770 
treatment in early AD. 
 
Treatment Assignment & Blinding 
In this randomized, double-blind, placebo controlled, 3-arm, parallel group study, 255 subjects will be 
assigned to receive one of three treatments via balanced randomization (1:1:1). Randomization will occur 
separately within each ApoE4 stratum (presence/absence of ApoE4 isoform) to ensure similar numbers of 
ApoE4 positive subjects are present in each treatment group. The three treatments are: 
A. BPN14770 10mg, twice-daily 
B. BPN14770 25mg, twice-daily 
C. Matched placebo, twice daily 
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 1 and receive their bottle of medication that 
same day. 
This is a randomized, double-blind study, meaning that neither site staff nor subject will know what the 
subject is receiving. Sponsor staff are also blinded to treatment assignments. 
Randomization codes will be provided to the Investigator or designee for use in case of an emergency 
code break requirement. Confirmation of receipt of the randomization code will be required by the 
Sponsor. The PI or designee 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. 
Except in the event of an emergency code break for an individual subject, 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. 
 
Administration of Study Medication 
Study drug will be taken by mouth (PO) with water (at least 120 mL = 4 ounces) in the morning and 
before bed. Subjects should attempt to take study drug at least 30 minutes prior to breakfast and at least 
one hour after dinner. The first dose should be taken one hour after dinner on Day 1. 


Statistical Analysis Plan  
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Study Procedures and Flowchart 
Table 2 shows the schedule of planned study procedures.  Every effort should be made to adhere to this 
procedure schedule. 
Table 2     Schedule of Assessments 
 
Screening 
Baseline 
Treatment 
Follow-Up 
 
Days -28 
thru Day 0 
Day 1 
Week 1 
Week 2 
Week 4 
Week 8 
Week 13e 
Week 14 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Target Study Day 
--- 
1 
7 
14 
28 
56 
91 
98 
Visit Window 
 
 
±2 
±2 
±2 
±3 
±3 
±3 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility Criteria Confirmed 
X 
X  
 
 
 
 
 
 
Medical/Surgical History 
X 
X 
 
 
 
 
 
 
Demographics and Social 
History 
X 
 
 
 
 
 
 
 
Full Physical Exam  
X  
 
 
 
 
 
X 
 
Abbreviated Physical Exam 
 
X 
 
 
 
 
 
X 
Height, Weight, BMI 
X 
Xa 
 
 
 
 
Xa 
 
Vital Signs b 
X 
X 
X 
X 
X 
X 
X 
X 
ECGs (single)   
X 
X 
X 
X 
X 
X 
X 
 
Serology (HbsAg, HCV) 
X 
 
 
 
 
 
 
 
Chemistry and Hematology 
X 
Xc 
X 
X 
X 
X 
Xc 
 
Lipids 
 
Xc 
 
 
 
 
Xc 
 
ApoE4 testing 
X 
 
 
 
 
 
 
 
Serum Pregnancy d 
X 
 
 
 
 
 
X 
 
Urine Pregnancy d 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
C-SSRS 
X 
X  
X 
 
X 
 
X 
 
RBANS 
X 
X 
X 
X 
X 
X 
X 
 
MMSE 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
 
   
 
X 
X 
 
CDR 
X 
 
 
 
 
 
X 
 
Hachinski (MHIS-NACC) 
X 
 
 
 
 
 
 
 
PK and Biomarker 
Sampling 
 
X 
(biomarkers 
only) 
X 
 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
Dispense Medication 
 
X 
 
X 
X 
X 
 
 
First Dose of Medication 
 
X 
 
 
 
 
 
 


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(PM dose 
following 
dinner) 
Daily Medication 
Administration BID 
 
 
X-------------------------------------------------------------X 
 
Medication accountability 
 
 
X 
X 
X 
X 
X 
 
Prior/Concomitant 
Medication Recording 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
X 
X 
X 
X 
X 
X 
X 
Final Disposition 
 
 
 
 
 
 
 
X 
a   Weight only  
b  Vital signs include pulse rate, blood pressure, respiration rate, and temperature  
c  Fasting for a minimum of 8 hours prior to blood draw is required at Baseline (Day 1) and End of Treatment (Week 13)  
d  All females of childbearing potential, even if using birth control)  
e  If a subject terminates from the study prior to Week 13, evaluations intended for Week 13 should be completed at discontinuation, 
if possible. 


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Endpoints 
 
Primary Efficacy Endpoint 
The primary efficacy outcome measure is the change from baseline to Week 13 in Repeatable Battery for 
the Assessment of Neurological Status - Delayed Memory Index (RBANS DMI). 
 
Secondary Efficacy Endpoints 
There are six secondary efficacy outcomes of interest. Change from baseline will be evaluated for each of 
the outcome measures below: 
• RBANS total score 
• Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory - Mild Cognitive 
Impairment version (ADCS-ADL) total score 
• Mini-Mental State Evaluation (MMSE) score 
• Clinical Dementia Rating sum of boxes (CDR-SB) score 
• Modified ADCOMS (m-ADCOMS) Composite Endpoint  
The observed values will be assessed for the endpoint below: 
• Clinical Global Impression-Improvement (CGI-I) score 
 
Safety Endpoints 
The following safety endpoints will be collectedduring the study. 
• Treatment-emergent adverse events 
• Vital signs 
• Clinical laboratory evaluations (chemistry, hematology, lipids, urinalysis) 
• Electrocardiogram (ECG) measurements 
 


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Analysis Populations 
 
Screened Population 
The Screened Population will include all screened subjects who signed the informed consent form. This 
population will be used for summaries of subject disposition, and listings unless otherwise specified. 
 
Randomized Population  
The Randomized Population will include the subset of subjects from the Screened Population who have 
been randomized. Subjects will be classified according to randomized treatment.   
However: Patient 
 was the same subject, randomized at 3 different 
treatment centers.  Due to the multiple treatments and overlapping treatment periods, this patient (and all 
3 patient numbers associated with the patient) is excluded from the Safety, modified intent-to-treat 
(mITT), Per Protocol (PP), Completers, and PK populations.  This patient will be reported in the CSR via a 
detailed patient narrative.  This patient is therefore excluded from ALL analysis populations. 
 
Safety Population  
The Safety Population will include all randomized subjects who received at least one dose of study 
treatment. Subjects will be analyzed according to treatment received.  Specifically, if a subject 
randomized to placebo takes one (or more) doses of active treatment (e.g., if the subject is dispensed the 
wrong drug kit at the site), the subject will be analyzed in that active treatment arm for all safety 
assessments. The Safety Population will be used for all analyses of safety endpoints. 
 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) Population will include all randomized subjects who received at least 
one dose of treatment and returned for at least one follow-up visit with the primary endpoint collected 
(non-missing). Subjects will be analyzed according to randomized treatment. The mITT Population will be 
used for all analyses of efficacy endpoints. 
 
Per Protocol Population  
The Per Protocol (PP) Population includes all mITT subjects who received at least one dose of treatment 
and returned for at least one follow-up visit with no significant protocol violations. Subjects will be 
analyzed according to randomized treatment. The PP population will be used to evaluate the robustness 
of the mITT results.  
 
PK Population  
The PK Population will include all subjects in the Safety Population who receive BPN14770, with at least 
one post-dose blood sample value with a non-missing (valid) plasma concentration of BPN14770. 
 
Completers Population 
The Completers  Population (CP) includes all mITT subjects who completed all 13 weeks of treatment 
with no significant protocol violations. The CP population will be used to evaluate the robustness of the 
ITT results. 


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Protocol Deviations 
A protocol deviation is any change or alteration from the procedures stated in the study protocol, consent 
document, recruitment process, or study materials (e.g., questionnaires). 
A major protocol deviation is a deviation that has an impact on subject safety, may substantially alter risks 
to subjects, may have an effect on the integrity of the study data, or may affect the subject’s willingness to 
participate in the study. Major protocol violations may include (but are not limited to): deviation from 
inclusion/exclusion criteria, withdrawal criteria met during the study but subject was not withdrawn, 
prohibited concomitant medications, treatment with incorrect study treatment (e.g., in the event a subject 
is accidentally given the wrong drug kit by the site), and substantial deviations from the dosing schedule. 
A minor protocol deviation is a deviation that does not impact subject safety, compromise the integrity of 
the study data, or affect the subject’s willingness to participate in the study. 
For this project, the protocol deviation collection will be managed in Clinical Trial Management System  
(CTMS) by the Site Monitors during the monitoring visits. The project team reviews the protocol deviation 
categories and classifications, and confirms these with the Sponsor on an ongoing basis. Protocol 
deviations will be summarized by classifications and categories on the Randomized Population. All 
protocol deviations will be listed. 
Protocol violations that result in exclusion from the PP population will be identified prior to unblinding.   
 
 


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General Aspects for Statistical Analysis 
 
General Methods 
Unless otherwise specified, continuous endpoints will be descriptively summarized with n, mean, 
standard deviation (SD), median, minimum (min) and maximum (max). The minimum and maximum will 
be reported with the same degree of precision (ie, the same number of decimal places) as the raw data. 
Mean and median will be reported to one degree of precision more than the raw data and standard 
deviation will be reported to two degrees of precision more than the raw data. In addition, change from 
baseline values will be calculated at each time point and summarized descriptively. For categorical 
endpoints, descriptive summaries will include counts and percentages.” See the programmings 
specifications at the end of this SAP (Section14) for more details.  
For tabulations, treatments will be sorted, left to right, as Placebo,  BPN14770 10 mg, and BPN14770 25 
mg.  In those cases where a combined column is needed, this will be at the far right as ‘Pooled 
BPN14770’ (if the 2 active arms) or ‘Total’ (if all 3 treatment arms). All analyses and summary outputs will 
be generated using SAS® version 9.4 (or higher). 
All subject data, including those derived as applicable, will be presented in the subject data listings; 
listings will display all subjects who were screened and have the related data collected. In general, the 
subject data listings will be sorted by treatment group, site (if site ID is not part of subject number), subject 
number and assessment visit and date (and time, if applicable). The summary tables will be presented 
descriptively by treatment groups and overall, if applicable.  
Unscheduled or repeat assessments will not be included in summary tables, but will be included in 
listings. Unless otherwise specified, if there are multiple results at a given visit/time point, the latest non-
missing value within the visit/time point window will be used.  
Where statistical models (e.g., mixed models for repeated measures (MMRM), analysis of covariance 
(ANCOVA)) are used to determine treatment effect estimates, least square means (LSmeans) and the 
standard error (SE) of the LSMeans will be presented.  Plots of changes over time in efficacy endpoints 
will present these LSMeans (SE) values.  Each of these statistical models will include all 3 treatment 
groups, and thus pairwise comparsions will be made with all treatments contributing to the error 
estimates. 
 
Key Definitions 
For the purposes of this study, the term “study drug” or “treatment” refers to BPN14770 or placebo. 
The study day is the day relative to the date of first dose of study drug. If the assessment date is on or 
after the date of first dose of study drug, the study day is calculated as date of assessment - date of first 
dose of study drug + 1 (and thus the day of first dose is designated as Study Day 1). If the assessment 
date is prior to the date of first dose of study drug, the study day is calculated as date of assessment - 
date of first dose of study drug (and thus the day prior to first dose is designated as Study Day -1). 
Unless otherwise specified, baseline is the last non-missing measurement before the first dose of the 
study drug, which is expected to be the baseline visit at Day 1, or screening if the Day 1 data are not 
available. 
The change from baseline will be calculated for each Post-baseline assessment as: 


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• 
Change from Baseline = Post-baseline value – Baseline value. 
 
Missing Data 
For the primary efficacy determination, observed cases data will be utilized. 
A supportive analyses will be performed for the primary efficacy endpoint to account for data missing at 
random (MAR) and for data missing not at random (MNAR).  MNAR data are often due subjects 
discontinuing due to lack of efficacy or to due treatment-emergent AE.  This sensitivity analysis will 
include the use of multiple imputation (MI).  Multiple imputation provides a useful strategy for analyzing 
data sets with missing values. Instead of filling in a single value for each missing value, Rubin’s (Rubin 
1987) multiple imputation strategy replaces each missing value with a set of plausible values that 
represent the uncertainty about the correct value to impute.  This analysis is described in the Primary 
efficacy endpoint section (Section 8.1.1). 
 
Visit Windows 
The visit windows are specified in the Schedule of Assessment in Section 3.7. The visits recorded in 
database will be used for the analyses, and there is no plan to re-assign visits based on actual visit dates, 
except the Early Termination (ET) visit. For ET visit, the next scheduled visit closest to the termination 
date will be assigned for the efficacy analysis specified in Section 8. 
 
Pooling of Centers 
Thirty eight (38) sites enrolled subjects into the study, with nearly 75% having enrolled < 10 subjects. As 
such, sites will be pooled based geographical location (based in US time zones: Eastern, 
Central/Mountain, Pacific) into pooled final site designations of at least 30 subjects per site. 
 
Subgroups 
Subgroup analysis of the primary efficacy endpoint will be performed for the following subgroups: 
• 
Presence or absence of the ApoE4 allele 
• 
By gender (male and female) 
• 
Ethnicity (Hispanic vs non-Hispanic) 
• 
MMSE (dichotomized as the baseline median across the pooled treatment groups) 
Tabulation of the incidence of TEAEs will also be presented for those subgroups. 
 
Data listings 
Data listings will be presented for all data collected.  The derived Study Day will be presented along with 
the date in these data listings.  Specifically for TEAEs and medications, the Study Start Day and Study 
Stop Day will be included.  Listings will be sorted by subject number, and then study visit or study day, 
accordingly. 


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
Subject disposition will be summarized for the Screened Population.   
For subject study status, the number and percentage of subjects for each one of the following categories 
will be presented by treatment groups and overall. 
• Screened subjects (Total only) 
• Screen failure subjects (Total Only)  
• Randomized Population  
• Safety Population 
• Modified Intent-to-Treat Population 
• Per Protocol Population 
• Completers Population 
• Subjects who completed the study 
• Subjects who discontinued the study prematurely by primary reason  
For all categories of subjects (except for the screened subjects and screen failures), percentages will be 
calculated using the number of randomized subjects as the denominator, unless otherwise specified. 
Subject disposition and analysis populations  data will be listed with clear indication of which populations 
in which each subject has been included. 
 
Demographic and Other Baseline Characteristics 
The following demographic and baseline variables will be summarized using the Safety Population and  
the mITT population, by treatment group and overall: 
• Age (years) 
• Age categorized (as <65, >=65 to <75, and >=75) 
• Gender  
• Race 
• Ethnicity 
• Body mass index (BMI) (kg/m2) at baseline 
• BMI categorized (dichotomized at <30 kg/m2 vs >= 30 kg/m2) 
• APOE4 test results (presence / absence of the allele) 
• Pre-treatment MMSE 


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• MMSE categorized as >=26, 23 to 25, <23 
• RBANS DMI 
• RBANS DMI by median overall (pooled across all treatment groups) <median vs >=median 
Modified Hachinski Ischemia Score (MHIS), smoking history, alcohol consumption, drug use, serology, 
and pregnancy test results will be collected and listed but not summarized. 
 
Medical/Surgical History  
Medical/surgical history as recorded at screening will be summarized using the Safety Population by 
treatment group using the number and percentage of subjects reporting each system organ class (SOC) 
and preferred term (PT). Medical/surgical history will be sorted by descending overall total by SOC and 
PT using the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary version 22.0 in the 
summary table. 
Medical/surgical history data will be listed and sorted by treatment group, site, subject number, onset 
date, SOC, and PT. 
 
Medication 
All concomitant medications taken 14-days prior to the first dose of study drug (Day 1) and during the 
study through the Week 14 Follow-up Visit should be recorded with indication, daily dose, and start and 
stop dates of administration. 
• 
Prior medications are those medications taken and stopped before the start of study drug dosing.  
• 
Concomitant medications are medications that are ongoing at or taken on or after the start of 
study drug dosing.  
• 
New-onset concomitant medications are defined as those medications starting between the first 
dose of double-blind study medication and 1 day (24 hours) after the start of the last dose of 
double-blind study medication.  Medications with no start time but starting on the day of double-
blind study medication will be assumed to be new-onset.   
Prior, concomitant, and new-onset medications will be summarized by the number and percentage of 
subjects taking a particular medication. All the medications will be listed. 
A summary of concomitant medications taken during the course of the study will be presented in tabular 
form using Anatomical Therapeutic Chemical (ATC) classification level 2 and PT via the World Health 
Organization Drug (WHODrug) Global B3 Mar 2019. The medications will be summarized using the 
Safety Population by treatment group and sorted alphabetically by ATC level 2 class and PT. If a subject 
has taken a medication more than once, the subject will be counted only once in the same ATC class or 
PT. 
Medications with incomplete end dates will be considered a concomitant medication if: 
• 
Day and month are missing and the year is equal to or after the year of the first dose date;  
• 
Day is missing and the year is after the year of the first dose; 


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• 
Day is missing and the year is equal to the year of the first dose date and the month is equal to or 
after the month of the first dose date; 
• 
Year is missing; or 
• 
Entire date is missing. 
The medication data will be listed, and sorted by treatment group, site, subject number, prior and 
concomitant status, onset date, ATC level, and PT. 


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Efficacy 
 
Primary Efficacy Endpoint and Analysis – RBANS DMI 
The Repeatable Battery for the Assessment of Neurological Status (RBANS) [Randolph 1998] is a brief, 
individually administered test measuring attention, language, visuospatial/constructional abilities, and 
immediate and delayed memory. It consists of 12 subtests, which yield five Index scores and a Total 
Scale score.    
Total scores are calculated by adding up the scores for each of the 12 individual subtests and ranges 
between 0 and 311, where a low score indicates greater impairment. The range of possible scores for the 
RBANS DMI is 40 to 160. 
The primary efficacy outcome measure is the change from baseline to Week 13 in the delayed memory 
index of the RBANS [Repeatable Battery for the Assessment of Neurological Status - Delayed Memory 
Index (RBANS DMI)].  Observed cases data (with no imputation for missing values) will be used for 
primary efficacy analysis. 
The original RBANS DMI score and change from baseline will be summarized by treatment group at each 
time point.  
The primary method of analysis will be an MMRM with restricted maximum likelihood estimation, an 
unstructured covariance matrix, and the Kenward-Roger approximation for denominator degrees of 
freedom.  The model will include fixed effects for treatment, visit (time), the treatment-by-time interaction, 
ApoE4, pooled study site, the baseline RBANS DMI score as covariate, and a random effect for subject.  
[Similar models will be defined for the other continuous secondary efficacy endpoints.]   Primary 
inferences will be drawn from treatment differences in the LSmean changes from baseline derived from 
the MMRM models at Week 13.  As additional supportive information, treatment differences for Weeks 1, 
4, and 8 will also be derived using the MMRM model.  Least Squares Means for each visit and the SE of 
the LSMeans will be displayed graphically. 
In an MMRM model, missing data are not explicitly imputed. Instead, all available postbaseline 
assessments up to endpoint for the subjects in the mITT population are utilized and, via modelling of the 
within subject correlation structure, endpoint treatment differences which are adjusted to take account of 
missing data are derived. The estimation of treatment differences using the MMRM model is based upon 
an assumption that the missing data follows a missing-at-random mechanism (i.e., the missingness of the 
observations may be dependent on the observed outcomes or covariates, but not on unobserved 
outcomes). For this primary analysis, no imputation of the missing values will be made or required and the 
data used in the analysis will be the actual observed responses at each visit. 
Exmaple SAS code: 
Proc Mixed data=indat ; 
 class trtp SITEGR1 ApoE4 avisitn subjid; 
 model chg=  base SITEGR1 ApoE4 trtp avisitn trtp*avisitn /ddfm=kr; 
 Random intercept / subject=subjid; 
 repeated avisitn / type=un subject=subjid; 
 lsmeans trtp*avisitn /cl diff ; 
run; 


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In the unlikely circumstance that there are convergence problems with the MMRM analysis, this will be 
explored.  For example, the SCORING=4 option could be used in the MIXED statement, which makes 
SAS use Fisher scoring for the first 4 iterations.  If the convergence problem cannot be resolved, the 
unstructured covariance matrix will be replaced by the AR(1) covariance structure in combination with a 
random subject effect. 
 
Sensitivity Analysis using Multiple Imputation (MI) Approach for the Primary Efficacy 
Endpoint of RBANS DMI 
A listing of the number of subjects with each unique missing pattern for the RBANS DMI will be 
presented.  This will be generated using PROC MI in SAS (see example, Table 3 ).  These data will be 
examined in order to determine if there was any general difference in the pattern of missing data between 
the treatment groups, as well as to explore the assumption of missingness at random. 
Table 3     Examples of Patterns of Missingness  
Pattern 
Treatment 
Group 
Number (%) of 
Subjects 
Baseline 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
13 
1 
25 mg 
xx (xx.x%) 
X 
X 
X 
X 
X 
X 
 
10 mg 
xx (xx.x%) 
X 
X 
X 
X 
X 
X 
 
Placebo  
xx (xx.x%) 
X 
X 
X 
X 
X 
X 
2 
25 mg 
xx (xx.x%) 
X 
X 
X 
X 
X 
. 
 
10 mg 
xx (xx.x%) 
X 
X 
X 
X 
X 
. 
 
Placebo  
xx (xx.x%) 
X 
X 
X 
X 
X 
. 
Etc. 
 
 
 
 
 
 
 
 
For the primary endpoint (RBANS-DMI), 100 imputed datasets will be created, with data imputation for 
missing values due to missingness at random as well as due to discontinuation due to AE or due to lack 
of efficacy  The 100 imputed datasets were analyzed using an analysis of covariance (ANCOVA) model 
with contrasts to test the primary efficacy endpoint.  The model used treatment as the main effect and 
stratification factor ApoE4, pooled study site and baseline RBANS-DMI as covariates.  Data from all three 
treatment groups were included in the same ANCOVA model for purposes of the testing procedures. 
The 100 resulting treatment effect parameters and standard errors (SEs) from these ANCOVA were 
presented individually and then combined to provide a distribution of parameters (and SEs) upon which 
the primary hypothesis of treatment effect was determined.   The results of the analyses were presented 
in summary tables with standard summary statistics as well as least squares (LS) means, active versus 
placebo LS mean differences (treated group – placebo), SEs, confidence intervals, and paired-
comparison p-values.  The mean RBANS-DMI values and standard errors of the mean (SEM) for each 
treatment group were also presented graphically.  This analysis was referred to as the multiple imputation 
analysis. 
Imputation Methodology:  
For subjects with arbitrary missing data patterns (missing at random [MAR]), here meant to represent 
RBANS-DMI scores that were missing for reasons other than the subject discontinuing (and specifically, 
‘intermediate time points’, eg, a subject has a valid non-missing Week 4 RBANS-DMI, but no Week 8, the 


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Week 8 score is considered MAR), a Markov chain Monte Carlo method (Schafer 1997) that assumed 
multivariate normality to impute all such MAR missing values was used to create preliminary imputed 
(resulting) data sets that have strictly monotone missing patterns.  A monotone missing pattern implies 
that all observations after a certain time point are missing, but that there are no intermediate missing 
values.  This pattern occurs when missing values are usually caused by subject discontinuation.  
After this first step, any subjects who had monotone missing values were then divided into two 
groups.  For subjects that did not discontinue due to an AE, a second imputation using regression-based 
method for continuous variables was then run to complete the imputed datasets by imputing the 
remaining monotone missing RBANS-DMI scores assuming MAR. 
For subjects with missing data as a result of discontinuation due to an AE the data was considered as 
missing not at random (MNAR).  The same pattern-mixture approach was also taken to the imputation (as 
for the monotone MAR data).  However, while a similar regression-based method for continuous variables 
was applied, a scaled (constant) adjustment to the imputed values was made such that the outcomes that 
were imputed were distributionally ‘worse’ than those imputed for the monotone MAR data.  This scaled 
adjustment increased each imputed value (from the regression) for these MNAR data by a constant of 
‘10’ (ten).  For example, if the regression provided an imputed value of 70 for a given missing value for a 
subject at a given time point, the MNAR imputed value was set to 70-10 = 60 for that subject at that time 
point.  This would, in effect, guarantee that the overall distribution of missing values for discontinuations 
due to an AE was WORSE than that for other reasons. 
Exapple SAS codes: 
Create the missing patterns of the data: 
proc mi data=dat nimpute=0;  
by trt01pn 
var Base Week1 Week2 Week4 Week8 Week13;  
ods output missPattern=pattern;  
run; 
Create monotone missing patterns under MAR assumption: 
proc mi data = non_mono out = monotone nimpute = 100 seed = xxx  
var trt01pn Base Week1 Week2 Week4 Week8 Week13;  
mcmc chain = multiple impute = monotone;  
run; 
Imputing the remaining monotone missing RBANS-DMI scores 
proc mi data=monotone out=imputed1 seed=xxx nimpute=1  
by _imputation_;  
class trt01pn ApoE4 Site;  
var trt01pn ApoE4 Site Base Week1 Week2 Week4 Week8 Week13;  
monotone reg(/details);  
run; 
Note: for data considered as MNAR, the imputed value will scaled via 
subtraction of ‘10’in order to ensure a ‘worse’ distribution than for 
data that is MAR. 


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Perform ANCOVA using imputed data: 
proc mixed data=imputed;  
by _imputation_;  
class trt01pn(ref='0') ApoE4 Site;  
model CHG = ApoE4 Site trt01pn base;  
lsmeans trt01pn /pdiff cl;  
ods output lsmeans=lsmeans diffs=diffs;  
run; 
Note: CHG is the change from baseline to Week 13 in RBANS-DMI. 
Combine the analysis results into a single estimation with standard error 
proc mianalyze parms=lsmeans;  
modeleffects trt01pn;  
ods output ParameterEstimates=lsm;  
by trt01pn;  
run; 
Sample SAS code presented above is for illustrative purposes, and the actual code may be adjusted as 
needed. Note that all imputed values will be ‘forced’ to fall into the range of ‘possible’ values for the 
RBANS-DMI (which ranges from 40 to 160).  
 
Additional Sensitivity Analysis for the Primary Efficacy Endpoint 
In addition, pooling of the two active BPN14770 arms will be performed and a comparison to the placebo 
arm will be  performed, using similar MMRM models as for the primary assessment, for the mITT 
population. 
The primary efficacy population will be the mITT population. The PP population and the CP population 
outcomes will be used to evaluate the robustness of the mITT results, using the models described above. 
A separate sensitivity analysis using a non-parametric (distribution-free) Wilcoxon Rank Sum Test of the 
pairwise treatment differences will be run for the Week 13 change from baseline data.  SAS code similar 
to the below will be used. A test of the normality of the residuals will be performed to assess the validity of 
the non-parametric vs parametric assumptions.The results will be presented in a summary table with 
standard summary statistics as well as the Wilcoxon rank sum means, active vs. placebo rank-sum mean 
differences and p-values.   
Proc npar1way data=dat; 
  Class treat; 
  Var change; 
  ods select WilcoxonScores; 
Run; 
 
 
Secondary Efficacy Endpoints and Analyses 
Change from baseline will be evaluated for each of the outcome measures below, using similar MMRM 
models as used for the primary efficacy endpoint. 


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• RBANS total score, as well as immediate memory, visuospatial/constructional, attention, and 
language indices 
• Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory - Mild Cognitive 
Impairment version (ADCS-ADL) total score 
• Mini-Mental State Evaluation (MMSE) score 
• Clinical Dementia Rating sum of boxes (CDR-SB) score 
• 
Modified ADCOMS (m-ADCOMS) Composite Endpoint.   
For the analysis of secondary efficacy endpoints, the primary efficacy population will be the mITT 
population. The PP population and the CP population may be used to evaluate the robustness of the 
mITT results if the mITT population is materially/substantially greater in sample size (ie, 10% or more) 
than those two populations. Otherwise, analyses for those two sensitivity populations will not be 
performed. 
An analysis of the Clinical Global Impression- Improvement (CGI-I) score will also be provided. 
 
RBANS total Score and other RBANS index scores 
The RBANS total score will be analyzed similarly as for the primary analysis for the primary efficacy 
endpoint in Section 8.1. The original RBANS total score and change from baseline will be summarized by 
treatment group at each time point. The LS Mean and SE of change from baseline in RBANS total score 
over time will also be presented graphically by treatment group. 
The pairwise differences in change from baseline between the treatment groups will be assessed at each 
time point.  
Age-based index scores are generated for each RBANS domain as well as a total scale, also expressed 
as an index score (normal mean=100; SD=15) that ranges from 40-160, calculated from the RBANS 
stimulus document.  Change from baseline in the other RBANS index scores (immediate memory, 
visuospatial/constructional, attention, language) will be summarized by time point, and analyzed similarly 
as the primany efficacy endpoint. 
 
ADCS-ADL Total Score 
The Alzheimer’s Disease Cooperative Study scale for ADL (ADCS-ADL) is administered by an 
independent rater. The ADCS-ADL is an interviewer-administered informant-based scale where the 
informant (caregiver) responds to 23 activities of daily living questions about the subject. The questions 
range from basic to instrumental activities of daily living and take approximately 20 minutes to complete. 
The total score ranges from 0-78 and a higher score signifies greater functional ability.   
Functional ability as assessed in any disease state, including AD, is typically described in terms of 
activities of daily living (ADLs) that are divided into broad conceptual categories of basic ADLs (BADLs) 
and instrumental ADLs (IADLs).  The ADCS-ADL is a 23 item scale that includes 6 BADL items and 17 
IADL items that provide a total score from 0-78, with a lower score indicating greater severity. Caregivers 
are asked to rate the degree to which their family member or loved one can perform a variety of tasks. 
Basic score will also be calculated as the sum of questions 1-6b and ranges from 0-22 (activities included 
in the basic score are: eating, walking, using the toilet, bathing, grooming and dressing) and Instrumental 


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score, sum of questions 7-23, ranges from 0-56. (activities included in the instrumental score are: using 
the telephone, watching television, conversations, clearing dishes, personal belongings, making drinks, 
making snacks, taking rubbish out, getting out and about, shopping, keeping appointments, being left 
alone, current events, reading, writing, pastimes/hobbies, household chores). 
The ADCS-ADL scores (total, as well as basic and instrumental sub-scores) will be analyzed similarly as 
for the primary analysis for the primary efficacy endpoint in Section 8.1. The ADCS-ADL scores and 
change from baseline will be summarized by treatment group at each time point. The LS Mean and SE of 
change from baseline in ADCS-ADL scores over time will also be presented graphically by treatment 
group. 
The pairwise differences in change from baseline between the treatment groups (will be assessed at each 
time point.  
 
Mini-Mental State Evaluation (MMSE) Score 
The Mini–Mental State Examination (MMSE) is a 30-point questionnaire that is used extensively in clinical 
and research settings to measure cognitive impairment. It is commonly used to screen for dementia. It 
consists of a series of questions and tests, each of which scores points if answered correctly. The MMSE 
tests a number of different mental abilities, including a person's memory, attention and language. 
The MMSE [Folstein 1975] consists of 11 items covering orientation, memory (recent and immediate), 
concentration, language and praxis. Scores range from 0 to 30, with lower scores indicating greater 
cognitive impairment.  Scores for each of the 11 individual tests are not recorded on the CRF, therefore if 
any item is missing then the total score will be set to missing.   
The maximum MMSE score is 30 points, with lower scores indicating worse disease.  A score of 20 to 24 
suggests mild dementia, 13 to 20 suggests moderate dementia, and less than 12 indicates severe 
dementia. On average, the MMSE score of a person with Alzheimer's declines about two to four points 
each year. (source:  https://www.alz.org/alzheimers-dementia/diagnosis/medical_tests) 
The MMSE scores will be analyzed similarly as for the primary analysis for the primary efficacy endpoint 
in Section 8.1, using an MMRM. The MMSE scores and change from baseline will be summarized by 
treatment group at each time point. The LS Mean and SE of change from baseline in MMSE scores over 
time will also be presented graphically by treatment group. 
The pairwise differences in LS Mean change from baseline between the treatment groups will be 
assessed at each time point.  
 
Clinical Dementia Rating Sum of Boxes (CDR-SB) Score 
The Washington University Clinical Dementia Rating scale [Morris 1993] is a structured, clinician-rated 
interview that collects information on cognitive capacity from both the collateral source and subject for the 
evaluation of staging severity of dementia. The CDR was developed primarily to assess severity level in 
persons with dementia but it can be used to stage dementia in other illnesses as well (eg, Parkinson's 
disease). Six domains are assessed and then synthesized to assign a Global CDR score. The domains 
are memory, orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care. Impairment is defined only when caused by cognitive loss rather than by physical disability 
or other non-cognitive factors.  Severity ratings range along a 5-point scale (except for the personal care 
domain): 


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• CDR-0: no cognitive impairment 
• CDR-0.5: questionable or very mild dementia 
• CDR-1: mild 
• CDR-2: moderate 
• CDR-3: severe 
The CDR is frequently utilized in clinical and research settings to describe stage-dependent features of 
dementia and for use as a clinically-meaningful outcome measure in clinical drug trials. 
CDR is an ordinal parameter (scale 0-3) and is only collected at baseline and Week 13. The CDR sum of 
boxes (CDR-SB) score is obtained by summing each of the domain box scores, with scores ranging from 
0 (least impairment) to 18 (severe impairment).   
The CDR-SB score (and each individual domain) will be analyzed similarly as for the primary analysis for 
the primary efficacy endpoint in Section 8.1. The CDR-SB score and change from baseline will be 
summarized by treatment group. The LS Mean and SE of change from baseline in CDR-SB scores will 
also be presented graphically by treatment group. 
The pairwise differences in change from baseline between the treatment groups will be assessed at 
Week 13.  
 
Clinical Global Impression- Improvement (CGI-I) Score 
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s condition 
posttreatment. The Investigator will rate the subject’s total improvement whether or not it is due entirely to 
drug treatment. Response choices include: 0=not assessed, 1=very much improved, 2=much improved, 
3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse.   
The CGI-I does not, by it’s very definition, have a baseline, and thus the model for this variable will not 
include a baseline covariate.  The CGI-I will be analyzed similarly as for the primary analysis for the 
primary efficacy endpoint in Section 8.1, with modification to the MMRM model accordingly. 
A table of the number (%) of subjects by each CGI-I response category will be provided for each study 
visit.  A CMH row means scores test (stratified by ApoE allele) will be provided at each time point.  
Further, at each time point, subjects will dichotomized as ‘improved’ or ‘not improved’, and p-values will 
be derived to test the treatment group comparibility accordingly (using a CMH test).   
The percentage of subjects with each score at each visit will also be presented graphically by treatment 
(via bar chart).  
An analysis will be performed by using PROC GLIMIX in SAS, and the cumulative odds ratios will be 
obtained by using the ESTIMATE statement. The difference between treatment groups will be evaluated 
by a generalized linear model (GLM) at each time point. The model will include fixed effects of ApoE4 
stratification factor, study site (pooled), and treatment group. The cumulative odds ratios will be presented 
along with the SE, a 95% CI, and the p-value. 


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Composite Endpoint 
The composite endpoint will be based on a modification to the AD Composite Score (ADCOMS), a 
composite clinical outcome for prodromal Alzheimer's disease trials [Wang 2016].   Since the 
assessments collected in this study were not the same as those collected in the published study, the 
statistician cited on the pubilication (S. Hendrix) assisted in the development of a modified ADCOMS (m-
ADCOMS) composite model for this study. 
A partial least square regression is performed and validated using data from the Alzheimer’s Disease 
Cooperative Study (ADCS) and from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The 
proposed model was derived using the original ADCOMS items [Wang 2016]  but leaving out the ADAS-
COG Word Finding Difficulty and the ADAS-COG Orientation, and substituting the RBANS immediate 
word recall (LRL) for the ADAS-COG Immediate Word Recall item (after dividing by the total points 
possible and multiplying by 10) and also the RBANS list recognition (LRN) for the ADAS-COG 
Recognition item (after dividing by the total points possible and multiplying by 12). The proposed model 
has an estimated mean square deviation ratio (MSDR) that is more than 95% of the original ADCOMS 
MSDR. 
The same weights as used for the original ADCOMS are used to calculate the composite score for this 
study: 
Composite =LRL*0.00847483 + LRN *0.003732761 + (5-M1)*0.041567 + (1-M7)*0.038238 + 
C1*0.054321 + C2*0.109100 + C3*0.089039 + C4*0.069493 + C5*0.058724 + C6*0.078152   
Scale 
Item ID 
Item Name 
RBANS 
LRL 
List Recall (LRL) 
  
LRN 
List Recognition 
MMSE 
M1 
Orientation Time 
M7 
Drawing 
CDR-SB 
C1 
Personal Care 
C2 
Community Affairs 
C3 
Home and Hobbies 
C4 
Judgment and Problem Solving 
C5 
Memory 
C6 
Orientation 
As the calculation of the composite scores needs to use the CDR-SB scores, which are only collected at 
baseline and Week 13, the composite scores will be analyzed similarly as for the primary efficacy 
endpoint at Week 13 only.  The composite scores and change from baseline will be summarized by 
treatment group. The LS Mean and SE of change from baseline in composite scores will also be 
presented graphically by treatment group. 
The pairwise differences in change from baseline between the treatment groups will be assessed and 
presented, using similar methology as for the primary efficacy endpoint.  
 
Multiplicity and Experiment-wise Alpha Control Considerations 
This is a Phase 2 dose-finding study, powered only for the primary efficacy endpoint; outcomes from this 
study are expected to be used to determine the dose to carry forward into Phase 3. Secondary efficacy 


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endpoints are expected to contribute data providing evidence of benefit from BPN14770 treatment and to 
be used as part of the preponderance of evidence in the dose-selection decision-making.  Due to the 
limited sample size in this Phase 2 dose-finding study, experiment-wise alpha control will be limited to 
control for the two pairwise tests for the primary efficacy endpoint only. 
• 
BPN14770 25 mg vs placebo 
• 
BPN14770 10 mg vs placebo 
A hierarchical approach will be taken, in which the 25 mg vs placebo comparison will be tested first, and 
only if statistically significant (p-value ≤0.05) will testing of the 10 mg vs placebo comparison be 
performed.  This will ensure alpha control of the primary endpoint for the study as well as a gated 
procedure for the secondary endpoints for each dose.  Only if the primary efficacy endpoint for a given 
dose is found to be statistically significant will the other efficacy endpoints will be tested at their nominal 
p-values, with no control for multiple testing.   
 


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Analysis Of Pharmacokinetics 
Plasma BPN14770 concentrations will be obtained during the Week 1, 4, 8 and 13 clinic visits. Samples 
will be drawn according to the time of the clinic visit, with documentation of time of day sampling was 
performed, and time of day of most recent dose of study medication.  
Plasma BPN14770 concentrations will be descriptively summarized by dose and visit for the PK 
Population. Concentration values below the lower limit of quantification (BLQ) will be treated as zero. 
A listing for Plasma BPN14770 concentrations with dose, visit, and collection time will be produced. 
 
 


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Analysis Of Biomarker Data 
Biomarker data will be analyzed post-study in an exploratory fashion.  This SAP does not 
address those analyses. 
 
 


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Safety 
The population used for safety analyses will be the Safety Population. Safety will be assessed on the 
basis of treatment-emergent adverse events (TEAEs), clinical laboratory values, vital signs, physical 
exams, the Columbia-Suicide Severity Rating Scale (C-SSRS), and ECGs. 
 
Extent of Exposure 
The following information will be summarized using descriptive statistics by the treatment group: 
• Duration of exposure (days) 
• Total number of capsules taken 
• Cumulative dose (mg) 
Duration of exposure will be calculated as: 
Date of last dose – date of first dose + 1. 
Total number of capsules taken will be calculated as: 
Sum of (Number of capsules dispensed at previous visit - Number of capsules returned) over all 
the visits. 
Cumulative dose will be calculated as: 
Total number of capsules taken X dose level 
The listing for the exposure data will be provided. 
 
Treatment Compliance  
Treatment compliance will be calculated for each visit and overall for the treatment period. 
Compliance (%) for each visit will be calculated as: 
(Number of capsules actually taken / Number of capsules planned) * 100% 
Number of capsules actually taken = Number of capsules dispensed at previous visit - Number of 
capsules returned/remained. 
Number of capsules planned = (current visit date – previous visit date)*2 – 1 (if last dose is in AM) + 1 (if 
last dose at previous visit is in AM). If last dose information is missing, last dose will be treated as AM 
dose. 
Compliance (%) for overall will be calculated as: 
(Total number of capsules taken / Total number of capsules planned) * 100% 


Statistical Analysis Plan  
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Total number of capsules taken is calculated as in Section 11.1; Total number of capsules planned is 
calculated as (Date of last dose – date of first dose) * 2. 
Compliance to study medication will be summarized using descriptive statistics for each visit and overall 
by treatment group. 
Compliance will also be listed along with the study medication accountability data. 
 
Adverse Events / Adverse Drug Reactions 
Adverse events (AEs), which include abnormal and clinically significant clinical laboratory test variables, 
will be monitored and documented from the time of Informed Consent until study participation is complete 
(the Follow-up Visit). 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 22.0.  The 
focus of the analysis will be on TEAEs, which will in general be summarized by treatment group and for 
the combined BPN14770 groups using preferred term (PT) and primary system organ class (SOC).  Pre-
treatment AEs will be listed (along with all the TEAEs, in the same listing), sorted by start day/date, but 
pre-treatment AEs will not be tabulated. 
TEAEs are defined as any AE that start on or after the first dose of the study drug, or any event that is 
present at baseline, continues after the first dose of the study drug, and worsens in severity or in 
frequency.  See Section 9.2.3 of the protocol for definition of serious adverse events (SAEs). 
Adverse events with incomplete start dates will be considered a TEAE if: 
• Day and month are missing and the year is equal to or after the year of the first dose date; 
• Day is missing and the year is after the year of the first dose;  
• Day is missing and the year is equal to the year of the first dose date and the month is equal to or 
after the month of the first dose date 
• Year is missing; or 
• Entire date is missing. 
If the relationship to study treatment or the severity (intensity) of the AE is missing, these will be left as 
missing, and the event will not be included in the tabulations for relatedness and intensity.   
For summaries by SOC and PT, a subject will be counted once at the SOC level and once at each PT 
within the SOC level. For summaries by SOC, PT, and maximum severity, a subject will be counted once 
at the highest severity level for which the event occurred at the SOC level and the highest severity level 
for each unique PT within that SOC level. Subjects will be counted only once within each SOC and PT at 
the strongest relationship to study drug in the following order: Related (possibly related, probably related,  
or related); Not Related (defined as unlikely related, unrelated, not related, no relation) to study drug. 
The summaries presenting frequency of TEAEs will be ordered by decreasing frequency of the combined 
BPN14770 groups by SOC and PT. 
Summary tables of TEAEs will summarize the number and percentage of subjects for the following: 


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• An overall summary of the number and percentage of subjects reporting TEAEs, study drug-related 
TEAEs, severe TEAEs, serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs 
leading to death. 
• TEAEs overall and by SOC and PT 
• Study drug-related TEAEs overall and by SOC and PT 
• TEAEs by maximum relationship to study treatment, overall and by SOC and PT  
• TEAEs by maximum severity, overall and by SOC and PT 
• Serious TEAEs, overall and by SOC and PT 
• TEAEs leading to study drug discontinuation, overall and SOC and PT 
Only TEAEs will be included in the summary tables, but all AEs will be listed. Separate listings for SAEs, 
TEAEs leading to study drug discontinuation, and TEAEs leading to death will also be provided . A 
separate listing of death events will also be provided.  All AE listings will include Study Day (start and 
stop) for the start dates and stop dates and will be sorted by Start Day. 
 
Laboratory Evaluations 
Blood samples for chemistry, hematology and lipid testing and urine samples will be collected based on 
the collection schedule provided in the Schedule of Assessments in Section 3.7 . A list of the clinical 
laboratory tests that will be performed can be found in Appendix 16.2 of the protocol. A central laboratory 
will be used to analyze the clinical laboratory samples. 
If laboratory values were considered clnically significant by the investigator, the value was to be reported 
as a TEAE, and thus clinically significant lab values are reported accordingly in the adverse events.   
Summary tables will include descriptive statistics for the actual values and changes from baseline by 
scheduled time point in hematology, chemistry, lipid testing, and quantitative urinalysis test results by 
treatment group. For qualitative urinalysis parameters, frequency counts and percentages will be 
presented over time for these categorical data by treatment. 
A shift table based on reported lab values classified as low/normal/high will be created for each lab 
parameter to assess shift from baseline to each subsequent visit. Similarly, a shift table comparing 
baseline lab value classification to shifts occurring anytime following initial dose by highest classification 
and lowest clarification will be provided.    
All parameters will be converted to consistent units according to the Standard International System of 
Units (SI) before summarization. 
All clinical laboratory results will be listed by site, subject and timing of collection. Out-of-range values will 
be flagged as low or high where applicable based on lab normal ranges provided by the lab(s). Listings of 
abnormal hematology and chemistry test results will be provided. 
All clinical laboratory parameters will be plotted over time (with mean and SD) by study visit.   


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Vital Signs  
Vital signs (pulse rate, blood pressure, respiration rate, and temperature) will be measured at Screening, 
during the Treatment Visits, and Follow-Up as specified in the Schedule of Assessments. Blood pressure 
at the Screening Visit should be obtained in both arms and the arm with the higher value should be used 
for ongoing monitoring throughout the rest of the study. For each subject, measurement on the same arm 
(right or left) using the same method (either automated or manual) should occur throughout the study. 
Summary table of actual values and changes from baseline by visit for each vital sign parameter will be 
provided by treatment groups. 
All vital signs measurement data will be listed by subject and time of measurement. Weight collected at 
Day 1 and Week 13 will be listed with vital signs. 
All vital sign parameters will be plotted over time (with mean and SD) by study visit. 
 
ECG 
Single 12-lead ECGs will be performed at clinic visits as specified in Table 2 Schedule of Assessments. 
Summary tables by visit and change from baseline to visit for each ECG parameter (Heart Rate, PR 
interval, QRS interval, QT interval, RR interval, and QTc interval) will be provided. 
The overall results of the ECGs recorded as “normal”, “abnormal, not clinically significant (NCS)” or 
“abnormal, clinically significant (CS)” will be summarized by treatment group at each visit. 
12-lead ECG data will be listed by subject and visit. 
The ECG analysis will include a careful review of QTcF values.  As part of this review, a summary of the 
number (percent) of subjects with QTcF values (at pre-treatment and then at any time post-first dose) in 
the following ranges will be provided:  ≤450 msec, >450 to ≤480 msec, >480 to ≤500 msec, and >500 
msec.  This will be performed by visit as well as at ANY time during the double-blind treatment period 
(where the highest QTcF value will be used for that assessment). 
 
Physical Examination 
The full physical examination will be conducting at the Screening and Week 13 (or Early Termination) 
Visits as specified in the Schedule of Assessments. An abbreviated physical examination will be 
conducted at on Day 1 (Baseline) and Week 14 Follow-Up. 
Significant findings prior to the start of dosing will be recorded on the Medical History page of the 
electronic case report form (eCRF). Only changes from baseline physical examination findings that meet 
the definition of a treatment-emergent AE will be recorded as an AE. 
Physical examination data will be listed only. 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a prospective assessment instrument that 
directly classifies suicidal ideation and behaviour into 11 preferred categories [Posner 2011]. The C-
SSRS involves a series of probing questions to inquire about possible suicidal thinking and behavior. 


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The C-SSRS will be conducted at Screening, Baseline, Week 1 and Week 4, as specified in the Table 2 
Schedule of Assessments. 
The C-SSRS data will be listed for all subjects. Listings will include behavior type and/or category for 
Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
The following outcomes are C-SSRS categories and have binary responses (yes/no). The categories 
have been re-ordered from the actual scale to facilitate the definitions of the composite and comparative 
endpoints, and to enable clarity in the presentation of the results. 
• 
Category 1 – Wish to be Dead 
• 
Category 2 – Non-specific Active Suicidal Thoughts 
• 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
• 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
• 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
• 
Category 6 – Preparatory Acts or Behavior 
• 
Category 7 – Aborted Attempt 
• 
Category 8 – Interrupted Attempt 
• 
Category 9 – Actual Attempt (non-fatal) 
• 
Category 10 – Completed Suicide 
• 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no). 
Endpoints based on the above categories are defined below.   
• 
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five suicidal 
ideation questions (Categories 1-5) on the C-SSRS. 
• 
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five suicidal 
behavior questions (Categories 6-10) on the C-SSRS.  
• 
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of the 
ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
• 
Self-injurious behavior without suicidal intent. 
A shift table to present changes from pre-treatment to any time post-first-dose will be assessed, with the 
number (and percent) of subjects showing a worsening from baseline on any of the four endpoints.   
The C-SSRS was collected at screening (and the assessment was based on subject recall from the past 
year), while on-treatment collection was based on outcomes ‘since the prior visit’.  Thus, the analysis will 
be done in two ways: 
1. 
Shifts from screening, where C-SSRS is relative to subject recall of the past year (using 
Screening value C-SSRS, and  shifts to each post-screening time point). 


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2. 
Shifts from baseline, where C-SSRS is collected relative to subject recall since the 
PREVIOUS visit, using Baseline value C-SSRS and shifts to each post-baseline time point). 
Table 4 presents the general manner in which these data will be tabulated. 
Table 4      Sample Table Demonstrating How C-SSRS Outcomes will be Presented  
 
 A listing of all C-SSRS data will be provided, while a listing of subjects who demonstrated a worsening on 
any one of the four endpoints will also be provided.  These listings will include the Study Day (relative to 
first dose of double-blind treatment) the C-SSRS was collected.   
 
 


Statistical Analysis Plan  
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Changes from Analysis Planned in Protocol 
There were no meaningful changes from the protocol described analysis.   


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Reference List 
1. Faraone, S.V. Interpreting estimates of treatment effects: implications for managed care. P T 33, 
700-711 (2008). 
2. Folstein M.F., Folstein S.E., McHugh P.R.. "Mini-mental state". A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. 
3. Karantzoulis, S., Novitski, J., Gold, M. & Randolph, C. The Repeatable Battery for the Assessment 
of Neuropsychological Status (RBANS): Utility in detection and characterization of mild cognitive 
impairment due to Alzheimer's disease. Arch Clin Neuropsychol 28, 837-844 (2013). 
4. Morris J.C. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology, 
November 01, 1993; 43 (11). doi: https://doi.org/10.1212/WNL.43.11.2412-a  
5. Posner, K, GK Brown, B Stanley et al., 2011, The Columbia-Suicide Severity Rating Scale (C448 
SSRS): Internal Validity and Internal Consistency Findings From Three Multi-Site Studies With 449 
Adolescents and Adults, Am J Psychiatry, 168:1266-1277. 
6. Randolph C., Tierney M. C., Mohr E., Chase T. N. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): Preliminary clinical validity. Journal of Clinical and 
Experimental Neuropsychology. 1998;20(3):310–319. doi:10.1076/jcen.20.3.310.823. [PubMed] 
7. Rogers, S.L., Farlow, M.R., Doody, R.S., Mohs, R. & Friedhoff, L.T. A 24-week, double-blind, 
placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. 
Neurology 50, 136-145 (1998). 
8. Rubin D.B.: Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and Sons, 
1987 
9. Seltzer, B., et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-
controlled trial. Arch Neurol 61, 1852-1856 (2004). 
10. Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: a composite clinical outcome for prodromal 
Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016;87(9):993–999. doi:10.1136/jnnp-
2015-312383. 
 
 


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Programming Considerations 
 
General Considerations 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format.  
• 
Numbering of TLFs will follow International Conference of Harmonization (ICH) E3 guidance. 
 
Table, Listing, and Figure Format 
 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
Treatments will be sorted, left to right, as Placebo, 10 mg, and 25 mg.  In those cases where a 
combined column is needed, this will be at the far right. 
• 
All TLFs will be produced using the Courier New font, size 8.  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (eg, μ). Certain subscripts and superscripts (e.g., cm2) will be employed on 
a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied 
formats, as appropriate. 
 
Headers 
• All output should have the following header at the top left of each page: 
Tetra Discovery Partners, Inc. 
Protocol No. BPN14770-CNS-201 
• All output should have Page n of N at the top or bottom right corner of each page. TFLs are 
internally paginated in relation to the total length (ie, the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page. 


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Display Titles 
• Each TLF should be identified by the designation and a numeral (ie, Table 14.1.1). ICH E3 
numbering will be followed. A decimal system (x.y and x.y.z) should be used to identify TLFs with 
related contents. The title is centered. The analysis set should be identified on the line immediately 
following the title. The title and table designation are single spaced. A solid line spanning the 
margins will separate the display titles from the column headers. There will be 1 blank line between 
the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Population 
 
Body of the Data Display 
14.2.4.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified; 
• Whole numbers (eg, counts) are right-justified; and 
• Numbers containing fractional portions are decimal aligned. 
14.2.4.2. 
Table Conventions 
• Units will be included where available 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so 
counts of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (eg, Medical History, Reasons for Discontinuation from the Study), 
then only those categories for which there is at least 1 subject represented in 1 or more groups are 
included. 
• An Unknown or Missing category is added to each parameter for which information is not available 
for 1 or more subjects.  


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• Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more significant digit than the original values, and standard deviations are printed out to 2 more 
significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
n 
  XX 
Mean (SD) 
XXX.X (XXX.XX) 
Median 
XXX.X 
Min,  Max 
XXX,  XXX 
• P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (eg, 7 (12.8%), 13 (5.4%)). Values that round down to 0.0. will be displayed as 
'<0.1', or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be displayed and 
percentages equating to 100% are presented as 100%, without decimal places.  
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC with the highest 
occurrence in the active treatment group in decreasing order, assuming all terms are coded. Within 
the body system, drug class and SOC, medical history (by preferred term), drugs (by ATC1 code), 
and adverse events (by preferred term) are displayed in decreasing order. If incidence for more 
than 1 term is identical, they should then be sorted alphabetically. Missing descriptive statistics or 
p-values which cannot be estimated are reported as “-”. 
14.2.4.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of treatment groups as above, subject number, 
visit/collection day, and visit/collection time. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on subject listings as dashes (--JUL2000). Dates that are missing because they are 
not applicable for the subject are output as “N/A”, unless otherwise specified. 
• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(eg, 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available. 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 


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• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source (ie, 
‘Program : myprogram.sas Listing source: 16.x.y.z’). 


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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health SOP Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of 
Biostatistical Deliverables (3908) describe the quality control procedures that are performed for all SAS 
programs and output. Quality control is defined as the operational techniques and activities undertaken to 
verify that the SAS programs produce the output by checking for their logic, efficiency and commenting 
and by review of the produced output.