Clinical trial NCT03493282
Conditions: Alzheimer Disease
Sponsor: Cognition Therapeutics
Start date: 2018-03-28; Completion date: 2020-10-16
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to Evaluate the Safety and Tolerability of Oral CT1812 in Subjects with Mild to Moderate Alzheimer's Disease.

Detailed description:
This is a single-center, randomized, double-blind, placebo-controlled, parallel group study of two doses of CT1812 in adults with mild to moderate Alzheimer's Disease to evaluate the safety and tolerability of oral CT1812, administered for up 180 days for the Primary study and another 180 days for the double-blind extension study.

Each participant and caregiver participated in a screening period of up to 60 days, followed by the primary double-blind treatment period of 24 weeks (169 days +/-2) followed by an optional double-blind extension treatment period of another 24 weeks (337 days +/-2).

Arms: arm 1: High Dose CT1812 arm 2: Low Dose CT1812 arm 3: Matching Placebo
Interventions: intervention 1: Active Treatment- CT1812 100 mg intervention 2: Active Treatment- CT1812 300 mg intervention 3: Placebo
Intervention descriptions: intervention 1: CT1812 intervention 2: CT1812 intervention 3: Matching Placebo

Protocol documents:
SAP_002.pdf: 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 1 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Statistical Analysis Plan  COG0105 
 
 
TITLE: A PILOT SYNAPTIC VESICLE GLYCOPROTEIN 2A (SV2A) PET STUDY TO 
EVALUATE THE EFFECT OF CT1812 TREATMENT ON SYNAPTIC 
DENSITY IN PARTICIPANTS WITH MILD TO MODERAT
DISEASE 
 
 
STUDY SPONSOR: 
 
SPONSOR CONTACT: 
 
Cognition Therapeutics, Inc. 
2403 Sidney St., Suite 261 
Pittsburgh, PA 15203 
USA 
 
 
Chief Science Officer 
Cognition Therapeutics, Inc. 
 
 
 
Email:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document History: 
 
 
 
Document 
Version 
Version Date 
Statistical Analysis Plan  COG0105 
Final 1.0 
11 Mar 2021 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT: 
 
 
All information concerning the study drug supplied by the Sponsor in connection with this study, 
and not previously published, is considered confidential and proprietary information. This 
informed consent, and case report forms. This confidential information shall remain the sole 
property of the Sponsor, shall not be disclosed to others without prior written consent from the 
Sponsor and shall not be used except in the performance of this study. 
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by the Sponsor in connection with the development of the study 
drug. This information may be disclosed as deemed necessary by the Sponsor. 
 
 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 2 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
This Statistical Analysis Plan has been prepared by Avance Clinical Pty Ltd (Avance) for the 
COG0105 study (Cognition Therapeutics, Inc.). The contents of this procedure are confidential 
and reproduction, in part or whole, is not permitted without prior written permission from 
Avance and the Sponsor. 
 
 
 
 
 
 
 
 
Prepared by:  
 
Date 
 
 Manager / Senior Biostatistician 
Avance Clinical Pty Ltd 
 
 
 
 
 
 
 
 
Reviewed by:  
 
Date 
 
Principal Biostatistician / Pharmacokineticist 
Avance Clinical Pty Ltd 
 
 
 
 
 
 
 
 
Approved by:  
 
Date 
 
Senior Clinical Advisor 
Cognition Therapeutics, Inc. 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 3 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
TABLE OF CONTENTS 
 
1. 
Scope of the Statistical Analysis Plan.................................................................................... 6 
2. 
Abbreviations ......................................................................................................................... 6 
3. 
Relevant Avance Standard Operating Procedures and Guidances ........................................ 7 
4. 
Introduction ............................................................................................................................ 7 
4.1. 
Study Overview .......................................................................................................... 7 
4.2. 
Study Objectives ......................................................................................................... 7 
4.3. 
Study Design ............................................................................................................... 8 
4.4. 
Study Treatment .......................................................................................................... 8 
4.5. 
Sample Size ................................................................................................................ 8 
4.6. 
Study Endpoints .......................................................................................................... 9 
5. 
Data Listings ........................................................................................................................ 10 
5.1. 
Sources of Data ......................................................................................................... 10 
5.2. 
Randomization and Subject Identification Code ...................................................... 11 
5.3. 
Maintaining the Study Blind ..................................................................................... 11 
5.4. 
Assessment Time Point Identifiers ........................................................................... 11 
5.5. 
Data Derived by Calculation .................................................................................... 11 
5.6. 
Handling of Missing Data ......................................................................................... 15 
5.7. 
Coding Abbreviations ............................................................................................... 17 
6. 
Analysis Populations ............................................................................................................ 17 
6.1. 
Safety Analysis Set ................................................................................................... 17 
6.2. 
Efficacy Analysis Set ................................................................................................ 18 
6.3. 
Pharmacokinetics Analysis Set ................................................................................. 18 
6.4. 
Pharmacodynamic Analysis Set ............................................................................... 18 
7. 
Subject Disposition/Background Data ................................................................................. 19 
7.1. 
Subject Disposition ................................................................................................... 19 
7.2. 
Baseline and Eligibility Assessments ....................................................................... 19 
7.3. 
Baseline Data Analysis ............................................................................................. 19 
8. 
Safety Data ........................................................................................................................... 20 
8.1. 
Safety Assessments ................................................................................................... 20 
8.2. 
Safety Data Presentation and Analysis ..................................................................... 20 
9. 
Efficacy Data ....................................................................................................................... 21 
9.1. 
Efficacy Assessments ............................................................................................... 21 
9.2. 
Efficacy Data Presentation ....................................................................................... 22 
9.3. 
Efficacy Analysis ...................................................................................................... 22 
9.4. 
Other Exploratory Efficacy Analyses ....................................................................... 23 
9.5. 
Adjustment for Multiplicity ...................................................................................... 25 
10. 
imaging outcomes ................................................................................................................ 25 
10.1. [11C] UCB-J PET Distribution Volume Ratio (DVR) .............................................. 25 
10.2. [18F]FDG PET SUV ratio (SUVR) ........................................................................... 26 
10.3. Volumetric MRI ........................................................................................................ 26 
10.4. Intrinsic Connectivity Contrast (ICC) ...................................................................... 27 
11. 
Pharmacokinetic/Pharmacodynamic Data ........................................................................... 28 
11.1. Pharmacokinetic Sample Collection ......................................................................... 28 
11.2. Pharmacokinetic Concentrations .............................................................................. 28 
11.3. Pharmacokinetic Parameters ..................................................................................... 29 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 4 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
11.4. Statistical Analysis of Pharmacokinetic Parameters ................................................. 29 
11.5. Pharmacodynamic Endpoints ................................................................................... 29 
11.6. Pharmacodynamic Analysis ...................................................................................... 30 
11.7. Statistical Analysis of Pharmacodynamic Parameters .............................................. 30 
11.8. Changes from the Analysis Planned in the Protocol ................................................ 30 
12. 
Data Listings and Summary Tables ..................................................................................... 30 
12.1. Interim/Preliminary Data Analysis ........................................................................... 30 
12.2. Listings and Tables for Clinical Study Report ......................................................... 30 
12.3. Data Transfer to the Study Sponsor .......................................................................... 30 
13. 
General Considerations for Data Management and Analysis .............................................. 31 
13.1. Analysis Packages .................................................................................................... 31 
13.2. Electronic Data Management ................................................................................... 31 
13.3. Archiving .................................................................................................................. 31 
 
 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 5 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
APPENDICES 
Appendix 1: Planned Data Listings ..................................................................................... 32 
Appendix 2: Planned Summary Tables ............................................................................... 34 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 6 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
1. SCOPE OF THE STATISTICAL ANALYSIS PLAN 
This Statistical Analysis Plan is an adjunct to Cognition Therapeutics, Inc. Protocol No. 
COG0105 dated 03 February 2021, Version 1.5. The Statistical Analysis Plan details the 
pre-planned procedures for the pharmacokinetic and statistical methods used in the 
analysis of the clinical data.  
Additional analyses may be explored as well upon review of the unblinded results and 
will be considered as post hoc analyses. 
2. ABBREVIATIONS 
AD  
 
 
ADAS-Cog  
Scale  cognition subscale 
ADCS-ADL  
 Activities of Daily Living 
ADCS-CGIC  
 Clinical Global Impression of 
 
 
Change 
AE 
 
Adverse event 
ANCOVA 
Analysis of covariance 
BMI 
 
Body mass index 
CDR-SB   
Clinical Dementia Rating Scale Sum of Boxes 
CRF 
 
Case report form 
DVR 
 
Distribution volume ratio 
ECG 
 
Electrocardiogram 
fMRI  
 
functional magnetic resonance imaging 
GDS  
 
Geriatric Depression Scale 
ICC 
 
Intrinsic Connectivity Contrast 
ICH  
 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
 
Investigational Product 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMSE 
 
Mini Mental State Exam 
NTB 
 
Neuropsychological Test Battery 
PD 
 
Pharmacodynamic 
PK 
 
Pharmacokinetic 
QA 
 
Quality assurance 
QC 
 
Quality control 
SAE 
 
Serious adverse event 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 7 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
SAP 
 
Statistical analysis plan 
SMC 
 
Safety monitoring committee 
SOP 
 
Standard operating procedure 
SUVR 
 
SUV ratio 
WHODrug 
WHO Drug Dictionary 
3. RELEVANT AVANCE STANDARD OPERATING PROCEDURES AND 
GUIDANCES 
The following Avance SOPs and regulatory guidances are relevant to this Statistical 
Analysis Plan: 
 SOP BIOM-0002 Clinical Data Analysis and Presentation  
 SOP BIOM-0003 Blinding: Codes and Code Breaking 
 SOP BIOM-0004 Randomisation Generation 
 SOP BIOM-0007 Pharmacokinetic Analysis Using WinNonlin 
 SOP BIOM-0009 Statistical Analysis Plans  
 ICH: Statistical Principles for Clinical Trials (ICH E9, Current Step 4 version 
dated 5 February 1998)  
 FDA: Bioavailability and Bioequivalence Studies for Orally Administered Drug 
Products  General Considerations (Revision 1, March 2003).  
 Bioavailability Studies Submitted in NDAs or INDs  General Considerations 
(latest draft February 2019) 
4. INTRODUCTION 
4.1. 
Study Overview 
This is a randomized, double-blind, placebo-controlled, parallel-group trial evaluating 
CT1812 with planned dose levels of 100 mg and 300 mg. 
4.2. 
Study Objectives 
Primary: 
 To evaluate the safety and tolerability of CT1812 in AD patients 
Secondary: 
 To evaluate the effect of CT1812 on brain synaptic density in AD patients using the 
SV2A PET ligand 11C-UCB-J. 
 To evaluate the effect of CT1812 on cognitive and clinical outcomes in AD patients 
using the ADAS-COG, NTB, derived cognitive composites, ADCS-ADL, MMSE, 
CDR-SB, and ADCS-CGIC  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 8 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 To evaluate the effect of CT1812 on brain activity in AD patients using FDG PET, 
resting state functional MRI 
 To evaluate the effect of CT1812 on brain volume in AD patients using volumetric 
MRI 
 To evaluate the effect of CT1812 on CSF pharmacodynamics in AD patients 
-tau, neurogranin, 
synpatosomal-associated protein-25 (SNAP25), synapotagmin, and NFL. 
Additional CSF biomarkers are listed in Section 11.5. 
 To evaluate the plasma and CSF concentrations of CT1812 in AD patients. 
Exploratory: 
 To correlate changes in synaptic density, other imaging endpoints and biomarkers, 
with cognitive function following CT1812 treatment. 
 To evaluate the plasma CT1812 metabolites in AD patients 
4.3. 
Study Design 
This is a single-center, Phase 1b, randomized, double-blind, placebo-controlled, parallel-
group trial in adults with mild to moderate AD. 
After consenting to participate in the study, screening procedures will occur between 
Days -60 and -1. Eligible participants will be randomized in a 1:1:1 (300 mg active: 100 
mg active: placebo) ratio.  The first dose of study drug will be administered in the clinic 
after all baseline procedures have been conducted. For the remainder of study days, 
participants will ingest study drug each morning at home. Participants and their study 
partners will return to the clinic for repeat psychometric/neurologic testing, safety 
studies, and PK and PD sample collection approximately every 2 weeks for the first 6 
weeks and then every 3 weeks thereafter up to 24 weeks for the primary study followed 
by an optional double-blind extension treatment period of an additional 24 weeks (337 
days +/-2) as well as a follow up visit at 2 weeks after the final treatment visit  
Participants who prematurely discontinue the study for any reason will be asked to attend 
a final safety and efficacy visit. 
4.4. 
Study Treatment 
CT1812 will be provided as a hydroxypropyl methylcellulose (HPMC) capsule 
containing 191 mg or 64 mg of CT1812 fumarate salt (equivalent to 150 mg or 50 mg of 
the CT1812 free base, respectively).    
Placebo capsules (containing of 191 mg or 64 mg of lactose monohydrate) will be 
supplied to match the CT1812 supplies in the same packaging. 
CT1812 or matching placebo will be administered once each morning as a 300 mg or 100 
mg oral dose (2 capsules).  
4.5. 
Sample Size 
Computation of sample size in this within-participant design was based on estimates of 
the magnitude of reductions in synaptic density from post-mortem AD data of 25-45%. It 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 9 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
was assumed that, on average, there is 30% loss of synapses in this population, and that 
CT1812 would restore one third of those synapses, with no change in synaptic density in 
the placebo group. Based on the excellent test/retest reliability of 11C UCB J, it was 
conservatively assumed 10% variability in baseline and post-treatment 11C UCB J 
binding potential non-displaceable (BPND) measurements. Power was first computed by 
assessing whether the change in synaptic density would be larger in the treated group 
than the placebo group.  
For group sizes of 7 per group, one has ~68% power for comparison of the combined 
treatment of N=14 CT1812 vs. 7 placebo subjects (  = 0.05, 1-tailed test). Higher power 
was present in the one-sample test of the treatment group, i.e., did synaptic density 
increase following CT1812 treatment. In that case, a group size of 7 CT1812 patients 
yields 80% power to detect an increase in synaptic density. Power for detecting changes 
in 18F FDG is likely to be lower since the magnitude of change in the SV2A signal in 
AD will be larger than that of 18F FDG (20%). 
4.6. 
Study Endpoints 
Safety Endpoints: 
 The incidence and severity of adverse events (AE) 
 The incidence of serious adverse events (SAE) 
 Changes in vital signs 
 Changes in physical and neurological exam findings 
 Changes in body mass 
 Changes in electrocardiogram (ECG) findings  
 Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis) 
 Changes in the Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Secondary: 
 The primary imaging endpoint is the change from the baseline in synaptic density 
as measured by differences in SV2A PET ligand 11C-UCB-J uptake after dosing 
with CT1812 versus placebo. 
 Cognitive and clinical outcomes: 
o Mini Mental State Exam (MMSE). 
o Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11 and 
ADAS-Cog13 (delayed recall and Number Cancellation added to ADAS-Cog11 
in the ADAS-Cog13); ADAS-Cog14 includes the maze added to ADAS-Cog13. 
o Neuropsychological Test Battery (NTB) including Trails A and B, Digit Span, 
and Letter and Category Fluency (CFT).  
o Alzheimer's Disease Cooperative Study (ADCS)-Clinical Global Impression of 
Change (CGIC). 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 10 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
o ADCS-Activities of Daily Living (ADCS-ADL). 
o Clinical Dementia Rating Scale  Sum of Boxes (CDR-SB) 
o Composite z-score scales (Cognitive Composite score; Memory composite 
score; Attention composite score; Executive Function composite score).  
o 
-tau, neurogranin, synaptotagmin, SNAP25, and NFL. 
 Imaging Outcomes 
o FDG PET 
o Functional MRI 
o Volumetric MRI 
Pharmacokinetic Endpoints: 
 The following CT1812 pharmacokinetic assessments will be made based on serial 
pre-dose concentrations in plasma and CSF: 
o CT1812 CSF/plasma concentration ratio 
o Changes in pre-dose CT1812 plasma concentrations  
o Plasma CT1812 metabolites 
5. DATA LISTINGS  
5.1. 
Sources of Data 
Data sets containing raw data will be provided by the Data Management group, extracted 
from the clinical study database of data entered into a Case Report Form. It is assumed 
that the database will contain the data from Screening through to the Follow-up Safety 
Visit of the study. 
Analysis datasets will be generated from the data extracted from the study database, 
along with the following data entered separately or received from other sources: 
 Randomisation/treatment assignment data, to be provided by the Avance 
unblinded statisticians 
 Clinical laboratory safety data, to be provided by Quest Diagnostics to Avance 
Clinical data management 
 CSF and plasma PK concentration data, to be provided by Agilex Biolabs 
 PD concentration data (CSF) data, to be provided by Agilex Biolabs 
All data entered into the CRF or provided from other sources as described above will be 
presented (explicitly or implicitly) in data listings or figures as described in Appendix 1. 
All available data collected for screen failed individuals will also be included in the 
individual data listings. 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 11 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
5.2. 
Randomization and Subject Identification Code 
This is a double-blind, placebo-controlled study. Study drug will consist of either of two 
doses of CT1812 or placebo. The placebo will be identical in appearance to both doses of 
the active CT1812.  
The non-blinded statistician assigned to the trial will generate a list with the appropriate 
number of 4 digit individual study IDs randomly for each arm, randomly assigned to 
either CT1812 300 mg, CT1812 100 mg or placebo treatment in a 1:1:1 ratio. 
Randomization will include a stratification factor for the MMSE score (18-22 or 23-26). 
The Randomisation Number will be specified as Rrnnn, where: 
 nnn = sequential subject id from 001 to 999, 
In the listings presenting the individual data, subjects will be identified by randomization 
number, with dose of CT1812 as a secondary grouping identifier. The screening number 
will be shown only on the listing of informed consent data. 
5.3. 
Maintaining the Study Blind  
In this double-blind study, all personnel involved, i.e. physicians, site staff, and 
participants will remain blinded at all times, except in an emergency where knowledge of 
the randomization code is required to provide appropriate treatment. The SMC will 
remain blinded but may break the blind for a given subject if deemed justified in 
accordance with the committee charter. 
Preparation of the randomization schedule in accordance with Avance SOP S-DM-004 
(Randomization) was performed by staff members of Avance who have no responsibility 
for monitoring and data management of this study. 
The individual data listings for inclusion in an appendix to the report will be prepared 
after the study has been unblinded.  
5.4. 
Assessment Time Point Identifiers 
In the data listings for the report, scheduled assessment time points will be identified as 
follows: 
 Scheduled safety assessments will be identified by treatment, study day, and also 
nominal study time point, where relevant. 
 Pharmacokinetic assessments will be identified by nominal time post-dose for the 
study treatment period. 
 Assessments at Screening and Study Completion visit will be identified as such for 
both study day and time-point, as appropriate. 
5.5. 
Data Derived by Calculation 
The following data fields for inclusion in the data listings will be derived by calculation: 
AEs Single Period: 
 Treatment-emergent Indicator for adverse event, assigned as 
Treatment-Emergent if  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 12 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
  (Onset Date + Onset Time) >= (Date of First Dose + Time of First Dose) 
 
Non Treatment-Emergent if 
  (Onset Date + Onset Time) < (Date of First Dose + Time of First Dose) 
 Adverse event time since first dose (in days, to two decimal places), calculated as  
(Onset Date + Onset Time)  (Date of First Dose + Time of First Dose) 
 Adverse event time since dose in current treatment period (in days, to two decimal 
places), calculated as  
(Onset Date + Onset Time  Date of Dose in Current Treatment Period - Time 
of Dose in Current Treatment Period)
AE Duration: 
 Adverse event duration (in days, to two decimal places), calculated as  
(Resolution Date + Resolution Time  Onset Date - Onset Time) 
Safety Assessments Change from Baseline: 
 Baseline for Vital Signs, ECG parameters, serum clinical laboratory parameters will 
be the most recent scheduled assessment prior to first dose 
Clinical Laboratory Assessments: 
 If a clinical laboratory result is above the upper limit of normal, then Out of Range 
 
 If a clinical laboratory result is below the lower limit of normal, then Out of Range 
 
 Clinical Laboratory parameters that are outside the reference range and assessed as 
 
 Clinical Laboratory parameters that are outside the reference range and not assessed 
 
Pharmacokinetics:  
 Actual collection time post-dose (in hours, to two decimal places) for PK blood 
samples for each dose day calculated as 
(Collection Date +Collection Time - Date of Dose - Time of Dose) 
Pharmacodynamics:  
 Actual collection time post-dose (in hours, to two decimal places) for PD CSF 
samples for each dose day calculated as 
(Collection Date +Collection Time - Date of Dose - Time of Dose) 
Efficacy Assessments Change from Baseline: 
 Baseline for ADAS-Cog11, ADAS-Cog13, ADAS-Cog14, NTB, ADCS-ADL, 
MMSE, CDR-SB, and ADCS-CGIC will be the most recent scheduled 
assessment prior to first dose 
Efficacy Assessments: 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 13 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 MMSE Total Score = sum of the individual scores from the 11 questions on the 
scale. 
 The ADAS-Cog11 total score = the sum of all 11 individual items (word recall; 
commands; constructional praxis; naming objects and fingers; ideational praxis; 
orientation; word recognition; remembering test instructions; spoken language; 
word finding; and comprehension of spoken language). The ADAS-Cog 11 will be 
considered the primary cognitive endpoint for this study. 
 The ADAS-Cog13 total score includes all of the items in the ADAS-Cog11 and the 
delayed word recall and the number cancellation.   
 The ADAS-Cog14 total score includes all of the items in the ADAS-Cog13 and the 
maze item.  
 The Cognitive Composite score will be calculated using z-scores of the below 
items. The z-scores will be derived by calculating the baseline mean and standard 
deviation of each individual component for all subjects. A z-score within each 
component will be derived for each subject at each timepoint by subtracting the 
corresponding baseline mean and then dividing by the corresponding baseline SD. 
The Cognitive Composite score will be set as the mean of the 10 individual z-
scores within each subject and timepoint. If a subject is missing one, two, or three 
scores at a particular timepoint, the missing scores will be set as the average non-
missing z-score of all subjects at that timepoint within each component when 
deriving the Cognitive Composite score. If a subject is missing four or more 
individual components at each timepoint, the Cognitive Composite score will not 
be derived. 
ADAS-COG 
Word recall (scored on a 0 to 30 range), sum of trials I, II, and III. If at 
least one of the trials is missing, this component will be considered 
missing. The sign of the z-score for this component will be reversed when 
deriving the Cognitive Composite score as it is the total words not recalled 
that is being recorded. This test is a key measure of episodic memory. 
Orientation (0 to 8). The sign of the z-score for this component will be 
reversed when deriving the Cognitive Composite score as the recorded 
score for this test is the number of items answered incorrectly. This 
single item of semantic memory (their name).  
Delayed Word Recall (0 to 10). The sign of the z-score for this component 
will be reversed when deriving the Cognitive Composite score as it is the 
total words not recalled that is being recorded. 
Word Recognition (0 to 24). The sign of the z-score for this component 
will be reversed when deriving the Cognitive Composite score. This is a 
further test of episodic memory using a word recognition paradigm of 12 
true positive targets and 12 foil items. While the possible score for this 
measure is 0 to 24, the standard ADAS-Cog score is capped at a maximum 
worst score of 12. 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 14 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Number Cancellation (0 to c.40). This test was added to the original 
ADAS-Cog to remedy the absence of an attentional test. Performance can 
range between a score of 0 and c.40. ADAS-Cog scoring requires that 
as 0 to 5 for ADAS-Cog scoring purposes. Having ensured that the total 
number of false alarms are comparable across both arms of the study, we 
will analyze total hits. If false alarms are unbalanced across study arms 
 
Maze - The ADAS-Cog14 augments the ADAS-Cog11 with delayed free 
recall, number cancellation, and maze-completion measures. A score of 0 
to 10 for delayed free recall and a conversion code of 0 to 5 for the digit 
cancellation and maze completion provides total score ranges for the 
extended ADAS-Cog14 from 0 to 90. The Maze item will be included as 
one of the components when deriving the Cognitive Composite and 
Attention Composite score.  The sign of the z-score for this component 
will be reversed when deriving these composite scores. 
NTB 
CFT  This is a further test of working memory and executive function 
responses are deemed acceptable according to the scoring rules. The usual 
performance range for this test is between 0 and 40. 
Digit Span  This is a brief measure of working memory, especially in the 
the test is 0 to 24 and both floor and ceiling effects are rare. 
Trail Making Test (TMT) A  This is essentially a measure of attention, as 
successful completion relies on quickly and accurately connecting 
numbered circles in an ascending sequence. The key metric for analysis 
nd time taken once again 
both contribute to performance. However, because errors incur a time 
penalty, it is not necessary to analyze both metrics. The sign of the z-score 
for this component will be reversed when deriving the Cognitive 
Composite score. 
TMTB  This is the more complex component of the TMT in which 
successful completion relies on the study participant accurately connecting 
the numbered and lettered circles. Study participants are required to 
alternate between numbers and letters in an ascending sequence. The key 
TMT A, because errors incur a time penalty, it is not necessary to factor in 
errors for analysis purposes. The sign of the z-score for this component 
will be reversed when deriving the Cognitive Composite score. 
 The Memory composite score will be a composite z-score average similar to the 
Cognitive Composite score, but will only be derived using the average of the 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 15 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
ADAS-Cog Word Recall, Orientation, Delayed Word Recall, and Word 
Recognition items. If a subject is missing any of the four items at a timepoint, this 
composite score will not be derived. 
 The Attention composite score will be a composite z-score average derived using 
the average of the Number Cancellation, Maze item from ADAS-Cog 14, and TMT 
A items. If a subject is missing either of the three items at a timepoint, this 
composite score will not be derived. 
 The Executive function composite score will be a composite z-score average 
derived using the average of the CFT, Digit Span, and TMT B items. If a subject is 
missing any of the three items at a timepoint, this composite score will not be 
derived.  
 
5.6. 
Handling of Missing Data 
The missing data for Cognitive composite is discussed in Section 5.5. 
 
For adverse events, where either the onset time or resolution time is unknown, time 
since first dose and duration will be imputed as follows: 
 If onset date is unknown, and it cannot be confirmed that onset was prior to the start 
of dose administration, then the AE will be classified as treatment-emergent, 
with unknown time since first dose. 
 If either the date of onset or the date of resolution is unknown, then duration will be 
shown as unknown. 
 If onset time is unknown: 
o If the date of onset is known to be the date of first dose administration, and it is 
confirmed by a CRF comment or communication with the site that onset was 
prior to the start of dose administration, then the AE will be classified as not 
treatment-emergent. 
o If the date of onset is known to be same as the date of first dose administration, 
and it is confirmed by a CRF comment or communication with the site that 
onset was after the start of dose administration, then Time since first dose will 
 
o If the date of onset is known to be later than the date of first dose 
administration, then Time since first dose will be determined as the number of 
of days difference between the date of dose administration and the date of 
onset. 
 If either the onset time or resolution time is unknown: 
o If the date of onset and the date of resolution are known to be the same, then 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 16 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
o If the date of onset and the date of resolution are known and are different, then 
Duration will be determined as the number of days difference between the date 
 
Baseline for safety assessments: 
 Missing values for safety assessments will not be imputed. If change from baseline 
is to be determined and the pre-dose baseline assessment is missing, then the 
previous scheduled result (e.g. Screening or Day -1) will be used as the 
baseline. However, if the baseline is missing due to technical reasons and a 
subsequent unscheduled pre-dose assessment is used to confirm eligibility, this 
unscheduled assessment may be used as baseline. 
Pharmacokinetic concentration and collection times: 
 Missing PK concentrations will not be imputed, except: 
o If the Day 1 pre-dose concentration is missing and the analyte is not 
endogenous, then a value of zero will be imputed; 
Efficacy missing data rules: 
 The ADAS-Cog11 total score ranges from 0-70 with higher scores indicating 
greater dysfunction. When the total score is missing due to non-cognitive 
reasons for one of the questions, the total score will be calculated as a weighted 
average of the scores provided for the remaining ten questions as follows: 
o Imputed Total= Observed Total Score * (1+ Maximum Score of the missing 
value / Sum of the Maximum Score of the non - missing values)  
 
Calculation of Imputed ADAS-Cog-11 Total Score  
Missing Question 
Imputed Total formula 
Word Recall 
Observed Total*(1+10/60) 
Orientation 
Observed total*(1+8/62) 
Word Recognition 
Observed total*(1+12/58) 
All other questions 
Observed total*(1+5/65) 
In cases where 2 or more questions are missing, the total score will not be imputed 
and will be set to missing. 
 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 17 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 The ADAS-Cog-13 total score ranges from 0-85. The imputed total score when 
there is only one item is missing due to non-cognitive reasons is presented 
below:  
 
Calculation of Imputed ADAS-Cog-13 Total Score 
Missing Question 
Imputed Total formula 
Word Recall 
Observed Total*(1+10/75) 
Orientation 
Observed total*(1+8/77) 
Word Recognition 
Observed total*(1+12/73) 
Delayed Word Recall 
Observed total*(1+10/75) 
All other questions 
Observed total*(1+5/80) 
 The ADAS-Cog-14 total score ranges from 0-90. The imputed total score when 
there is only one item is missing due to non-cognitive reasons is presented 
below:  
 
Calculation of Imputed ADAS-Cog-14 Total Score 
Missing Question 
Imputed Total formula 
Word Recall 
Observed Total*(1+10/80) 
Orientation 
Observed total*(1+8/82) 
Word Recognition 
Observed total*(1+12/78) 
Delayed Word Recall 
Observed total*(1+10/80) 
Maze 
Observed total*(1+12/78) 
All other questions 
Observed total*(1+5/85) 
 No further imputation for efficacy assessments. In order to have all subjects with 
any non-missing efficacy data contributing to the analysis, a mixed model for 
repeated measures (MMRM) will be used to take the missing data into account. 
Under the assumption that missing data are missing at random, inferences 
based on methods of MMRM estimation in mixed models are valid. 
5.7. 
Coding Abbreviations 
Any coding abbreviations used in data listings will be included in the key in a footnote, 
as appropriate. 
6. ANALYSIS POPULATIONS 
6.1. 
Safety Analysis Set 
The safety analysis set will include all subjects who were administered with the 
investigational product (IP), including those who may have withdrawn prior to study 
completion.  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 18 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Safety data will be presented for all subjects in the safety analysis set, and summarised by 
treatment group. 
Subject disposition and background data, including demographics, relevant background, 
participation and compliance data, will be presented for all subjects in the safety analysis 
set. 
Participants who are assigned a randomization number but withdraw prior to dosing will 
not be included in the safety analysis set. Available details of their participation and 
reason for withdrawal will be listed separately. 
6.2. 
Efficacy Analysis Set 
Efficacy data will be presented for all subjects who were administered with the IP, 
including those who may have withdrawn prior to study completion.  
The full analysis set (FAS) for efficacy will include all subjects who receive IP and who 
have at least one post-dose assessment of any of the cognitive and clinical endpoints.  
Summaries of efficacy assessments will be presented for the FAS analysis set, by 
treatment group. 
6.3. 
Pharmacokinetics Analysis Set 
Pharmacokinetic concentration data will be listed and presented graphically for all 
subjects who were administered with active IP, including those who may have withdrawn 
prior to study completion. Pre-dose trough plasma concentrations will be determined for 
all subjects IP in the pharmacokinetics analysis set, noting that this may be not applicable 
on a scheduled sampling day for subjects from whom PK sample collection was not 
completed.  
The per protocol pharmacokinetic analysis set will include all subjects in the PK Analysis 
Set who have no major protocol violations that impact on pharmacokinetics. Subjects 
who do not complete the sampling per schedule, but pre-dose trough samples on at least 
one visit day (after Day 1), will be evaluated. Data from subjects who experience emesis 
on the day prior to pre-dose trough sample collection at, or before, two times the tmax 
observed in previous studies (2 hours post-dose) may be deleted from statistical analysis.. 
Summaries of concentration data will include only subjects in the per protocol 
pharmacokinetic analysis set. Pharmacokinetic concentration data will be summarised by 
treatment group. 
6.4. 
Pharmacodynamic Analysis Set 
Pharmacodynamic data will be presented for all subjects who were administered with IP, 
including those who may have withdrawn prior to study completion.  
The per protocol pharmacodynamic analysis set will include all subjects who receive IP 
and who have at least one post-dose result for any CSF concentrations.  
Summaries of pharmacodynamic assessments will be presented for the Pharmacodynamic 
analysis set, by treatment group. 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 19 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
7. SUBJECT DISPOSITION/BACKGROUND DATA 
7.1. 
Subject Disposition  
Subject disposition and administration procedures recorded in the CRF are as follows: 
 Written informed consent 
 Randomization 
 Administration of IP 
 Study completion /discontinuation 
 Protocol deviations 
 Additional comments 
Details of participation and inclusion in analysis populations will be listed by subject. 
Completion status will be summarised by treatment group. 
Details of administration of IP will be listed by subject. Exposure to IP will be 
summarised by treatment group. 
Protocol deviations will be listed by subject. A summary of protocol deviations will be 
prepared for inclusion in the clinical study report. 
7.2. 
Baseline and Eligibility Assessments 
Baseline and eligibility assessments are as follows: 
 Demographic details 
 Medical, Surgical and Psychiatric history 
 Physical examination 
 Eligibility 
 Serology (HIV, Hepatitis B and C) 
 Pregnancy Tests 
 Blood sampling for Apolipoprotein E (ApoE) genotyping 
 Modified Hachinski exam 
 Geriatric Depression Score (GDS) 
 Alzheimer's Disease Diagnosis 
7.3. 
Baseline Data Analysis 
Demographics will be listed individually by subject and summarised by treatment group 
and overall.  
Medical history and physical examination data at baseline and results of tests performed 
for eligibility will be listed by subject.  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 20 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Baseline assessments of on-study measures will be listed and summarised along with 
post-dose assessments, as described below. 
8. SAFETY DATA 
8.1. 
Safety Assessments 
Safety assessments are as follows: 
 Adverse events and concomitant medications used: 
o Continuous monitoring throughout the study period 
 Vital signs: 
o Body temperature, seated systolic and diastolic BP, pulse rate and respiratory 
rate 
 Body mass 
 Clinical laboratory tests: 
o Hematology - red blood cell count, erythrocyte mean corpuscular haemoglobin 
concentration (MCHC), erythrocyte mean corpuscular volume (MCV), 
hematocrit, hemoglobin, leukocyte count, and absolute counts of monocytes, 
neutrophils, basophils, eosinophils and platelets 
o Chemistry - glucose, calcium, albumin, total protein, sodium, potassium, 
bicarbonate, chloride, magnesium, BUN, creatinine, creatine kinase, alkaline 
phosphatase, ALT, AST, bilirubin, lipase, lactate dehydrogenase (LDH) and 
phosphorus 
o Coagulation INR, prothrombin time. 
o Urinalysis  osmolality, creatinine, calcium, sodium, turbidity, color, specific 
gravity, pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, nitrite, 
leukocytes, and microscopic particles 
o Thyroid Tests  TSH, T3, T4 
 ECG (ventricular rate, PR, QRS, QT, 
 
 Physical examination including all major organ systems (exception: genitourinary 
and reproductive should be symptom-directed). 
 Symptom Directed Neurological Examination 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
8.2. 
Safety Data Presentation and Analysis 
All clinical safety and tolerability data will be listed for each subject.  
Safety data will be summarized using descriptive statistics. Where summaries include 
changes from baseline, the relevant baseline value will be determined as described in 
Section 5.5 above.  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 21 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
All treatment-emergent adverse events reported in this study will be listed using 
MedDRA terms, as coded per the Data Management Plan. The number of subjects 
reported with AEs and the number of AEs reported following administration of the IP 
will be summarised by treatment, grouped according to system organ class and preferred 
term, using descriptive statistics. The order for system organ class will be according to 
the Internationally Agreed Order, as per the guidance document MedDRA® Data 
Retrieval and Presentation: Points to Consider, specific to the MedDRA version used for 
this study. Summaries of AEs will also be presented by severity and by relationship to 
investigational product.  In these summaries, subjects will be counted only once per 
MedDRA term, for the AE of highest severity or least favourable relationship. 
Summaries will also be presented of SAEs and of AEs leading to study withdrawal. 
Clinical laboratory parameters for clinical chemistry, hematology, coagulation, urinalysis 
and thyroid tests will be listed and summarised by treatment group and study timepoint. 
Medical assessments of blood and urine parameters will be summarised by treatment 
group and study timepoint. A summary of changes from baseline will also be presented 
for serum clinical laboratory parameters. Individual subject profiles will be presented for 
any laboratory parameters with at least one post-dose 
reference ranges and deemed clinically significant. 
Vital signs will be listed and summarised by treatment and study timepoint. A summary 
of changes from pre-dose baseline will also be presented. 
Body mass will be listed and summarised by treatment and study timepoint. In addition, a 
summary of changes from pre-dose baseline will be presented. 
ECG parameters will be listed and summarised by treatment and study time point. A 
summary of changes from pre-dose baseline will also be presented. For QTcB the 
number of subjects with values greater than 450 (and 480, 500) msec or an increase from 
baseline of at least 30 (and 60) msec will also be presented, in accordance with ICH E14 
(Note for guidance on the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs, CHMP/ICH/2/04). 
Changes in physical examination findings over time will be listed by body system for 
each subject. It is noted that any untoward findings identified on physical examinations 
after the administration of the first dose of study medication will be captured as an 
adverse event if those findings meet the definition of an adverse event as defined in the 
protocol. 
Changes in neurological examination findings over time will be listed by neurological 
system for each subject. 
Changes in the Columbia Suicide Severity Rating Scale (C-SSRS) will be listed for each 
subject. 
9. EFFICACY DATA 
9.1. 
Efficacy Assessments 
Efficacy is assessed by the cognitive and clinical outcomes ADAS-Cog, NTB, ADCS-
ADL, MMSE, CDR-SB and ADCS-CGIC scales, measured at the following timepoints: 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 22 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 V1 (Study Day -60 to -1)/Step 1 (MMSE only) 
 Baseline V2 (Study Day 1) (excluding MMSE) 
 V5 (Study Day 43) 
 V7 (Study Day 85) 
 V9 (Study Day 127) 
 Final/Early Discontinuation V11 (Study Day 169) (for subjects participating in the 
Primary Study Only) 
 V11 (Study Day 169) (for subjects participating in the Extension Study) 
 V13 (Study Day 253) (for subjects participating in the Extension Study) 
 Final/Early Discontinuation V15 (Study Day 337) (for subjects participating in the 
Extension Study) 
9.2. 
Efficacy Data Presentation  
All cognitive and clinical assessments for each subject will be presented in individual 
data listings. 
For the ADAS-Cog (sub) scales, the total score for the corresponding items will be 
calculated as per Section 5.5. The total score and the Change from Baseline in the total 
score will be included in the individual data listings. Both the total score and the change 
from baseline will be summarized by visit and treatment group. Observed Mean change 
from Baseline (+/- SD) in ADAS-Cog total scores will be presented graphically by 
treatment group over time. 
For NTB, the total time (in seconds) taken to complete both Trail A and Trail B will be 
presented in the same way as for the ADAS-Cog total score, as described above. 
The total score for ADCS-ADL, for MMSE and for CDR-SB will be presented in the 
same way as for the ADAS-Cog total score, as described above. 
The Composite z-score scales will be presented for each scale, in the same way as for the 
ADAS-Cog total score, as described above. 
For ADCS-CGIC, the individual data listing will present the original score on the 
seven-point scale. In addition, the seven-point score will be collapsed to 3 groups, 
combining scores 1-3 to 
, 
No change
-
Worsening . This 
derived three-point scale will also be included in the individual data listing.  
For the seven-point scale and the derived three-point scale, the number of subjects in 
each of the categories will be summarized by visit and treatment group using counts and 
percentages. 
9.3. 
Efficacy Analysis 
The change from baseline in the composite scores and clinical outcomes will be analyzed 
using a mixed effects model including fixed effects for treatment group (i.e. 300 mg 
active, 100 mg active, placebo), visit and treatment by visit interaction. In addition, the 
 score will be included as a covariate. For each time point up to and 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 23 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
including 6-months, the treatment differences between 300 mg active and placebo, and 
100 mg active and placebo will be estimated from the model. In addition, the low and 
high CT1812 dosed groups will be pooled and compared with the placebo group. This 
analysis will be considered the primary analysis.  
A separate pooled analysis and analysis by arm will also be performed for time points up 
to and including the 12-month time point. 
Additionally, p-values and corresponding two-sided confidence intervals will be 
provided. The LS Mean Change from Baseline in ADAS-Cog total scores with 95% CI 
will be presented graphically by treatment group over time. 
In the event that a scale or parameter only has a single post-baseline timepoint, an 
ANCOVA model will be run in place of the MMRM model without the visit and visit by 
treatment interaction terms. The ANCOVA model will include a fixed effect for 
treatment group, and the subje
 For parameters for 
which there are multiple post-baseline timepoints, ANCOVA models such as that just 
described above may also be run in addition to the MMRM model at various timepoints. 
The change from baseline in the ADAS-Cog (sub) scale total score, total time (in 
seconds) taken to complete both Trail A and Trail B in the NTB, ADCS-ADL total score, 
MMSE, CDR-SB, and composite scores will be analysed using the MMRM model 
described above.  
To compare 300 mg active vs placebo and 100 mg vs placebo statistically, observed 
values for ADCS-CGIC will be analyzed using the MMRM model described earlier 
without the baseline term. Additionally, frequencies and percentages in the ADCS-CGIC 
will be summarized by visit. Cochran-Mantel-Haenszel mean score statistics, using rank 
scores will be used to assess the difference in ADCS-CGIC responses at each visit 
between the CT1812 dose levels and placebo. 
9.4. 
Other Exploratory Efficacy Analyses 
Pearson correlation coefficients will be used to assess associations between imaging 
endpoints, CSF biomarkers and cognitive and behavioral changes (ADAS-11, ADAS-13, 
ADAS-14, Cognitive Composite, Memory Composite, Executive Function Composite, 
Attention Composite, NTB individual items, MMSE, CDR-SB, ADCS-ADL, and ADCS-
CGIC). Correlations will be calculated for baseline imaging and biomarker values and 
baseline efficacy measures. Additionally, correlations between change from baseline in 
by-visit imaging and biomarker values and change from baseline in efficacy scales will 
be calculated. 
The composite imaging parameters that will be used for the correlations with the 
cognitive and functional endpoints include: the DVR composite region, the FDG 
composite region, the volumetric MRI composite region and the ICC composite region. 
Additionally, for volumetric MRI the cerebral cortex region and the lateral ventricles will 
also be included. For all imaging modalities the following individual parameters will also 
be included: 
 Hippocampus 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 24 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 Entorhinal cortex 
 Parahippocampal corte 
 Amygdala 
 Fusiform gyrus 
 Lingual gyrus 
 Inferior/middle temporal cortex 
 Anterior cingulum 
 Posterior cingulum 
 Precuneus 
 Prefrontal cortex 
 Superior temporal cortex 
 Lateral parietal cortex 
 Lateral occipital cortex 
 Pericentral cortex 
 Medial occipital cortex 
 
The CSF parameters that will be used for the correlations with the cognitive and 
functional endpoints include:  
 
 monomer 
 
 monomer 
 Tau 
 phospho-tau 
 neurogranin 
 Synaptotagmin 
 synpatosomal-associated protein-25 (SNAP25) 
 NFL 
 YKL-40 ELISA 
 
 
Additional CSF exploratory biomarkers that will be used for the correlations of the 
cognitive and functional endpoints include:  
 
 neuronal pentraxin-1 
 neuronal pentraxin -2 
 neuronal pentraxin receptor 
 complexin-2 
 syntaxin-1b 
 sytaxin-7 
 gamma-synuclein 
 rab GDI alpha 
 Phosphatidylethanolamine-binding protein 1 
 AP-2 complex subunit beta 
 14-3-3 protein zeta/delta 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 25 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Additional exploratory plasma biomarkers and CSF biomarkers such as CSF 
 oligomers and other phospho-tau species may be analyzed later when these results 
become available and may be included as a supplementary appendix to the CSR. 
CT1812 concentrations in CSF and plasma will also be correlated with changes in 
biomarkers and cognitive measures.  
Additional analyses and correlations may be explored as well (e.g., possibly including 
age, gender, education and ApoE) and will be discussed in the clinical study report 
(CSR). 
9.5. 
Adjustment for Multiplicity 
No adjustments for multiplicity will be made. 
10. IMAGING OUTCOMES 
The change from baseline in the outcome will be compared between the treatment groups 
using the MMRM or ANCOVA model described in section 9.3.  
The pooled analysis and analysis by arm will be performed with data for the composite 
regions and for the individual exploratory regions collected for points up to and including 
the 6-month time point. This analysis will be considered the primary analysis. 
A separate pooled analysis and analysis by arm will also be performed with data for the 
composite regions and for the individual exploratory regions at time points up to and 
including the 12-month time point. 
10.1. 
[11C] UCB-J PET Distribution Volume Ratio (DVR) 
For 11C-UCB-J, the primary imaging outcome measure is DVR as produced by the 
Simplified Reference Tissue Model (SRTM2) using dynamic scan data from 0 to 60 min 
and the whole cerebellum as a reference region. For DVR, a composite region will be 
determined, including: prefrontal, lateral temporal, posterior cingulate/precuneus, anterior 
cingulate, lateral parietal, medial temporal, and lateral occipital regions. For the 
11C-UCB-J DVR outcome composite region the primary model will be analyzed without 
reference to age and ApoE4 status, however additional models will be run that include 
age and ApoE4 status as sensitivity analyses. Analyses will also be conducted to assess 
the relationship of age and ApoE4 status with the dependent DVR variable and to 
determine if there is any imbalance on these variables between the treatment groups. 
Regional analyses will first focus on the hippocampus since the recent cross-sectional 
study has shown this to be the region of largest group differences in synaptic density 
when comparing a group of participants with AD to healthy participants. 
Individual exploratory regions include: 
 Hippocampus 
 Entorhinal cortex  
 Parahippocampal cortex 
 Amygdala  
 Fusiform gyrus 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 26 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 Lingual gyrus 
 Inferior/middle temporal cortex  
 Anterior cingulum 
 Posterior cingulum 
 Precuneus 
 Prefrontal cortex 
 Superior temporal cortex 
 Lateral parietal cortex 
 Lateral occipital cortex 
 Pericentral cortex 
 Medial occipital cortex 
10.2. 
 [18F]FDG PET SUV ratio (SUVR) 
For 18F-FDG, the primary imaging outcome measure is the SUVR from 60-90 min post 
injection using whole cerebellum as a reference region.  For SUVR, a composite region 
will be determined, including: prefrontal, lateral temporal, posterior cingulate/precuneus, 
anterior cingulate, lateral parietal, medial temporal, and lateral occipital regions. 
Individual exploratory regions include: 
 Hippocampus 
 Entorhinal cortex  
 Parahippocampal cortex 
 Amygdala 
 Fusiform gyrus 
 Lingual gyrus 
 Inferior/middle temporal cortex 
 Anterior cingulum 
 Posterior cingulum 
 Precuneus 
 Prefrontal cortex 
 Superior temporal cortex 
 Lateral parietal cortex 
 Lateral occipital cortex 
 Pericentral cortex 
 Medial occipital cortex 
10.3. 
Volumetric MRI 
A composite region of AD affected brain regions will be determined, including: 
prefrontal, lateral temporal, posterior cingulate/precuneus, anterior cingulate, lateral 
parietal, medial temporal, and lateral occipital regions. An additional cerebral cortex 
region will also be analyzed. 
 
Individual exploratory regions include: 
 Hippocampus 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 27 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 Entorhinal cortex 
 Parahippocampal corte 
 Amygdala 
 Fusiform gyrus 
 Lingual gyrus 
 Inferior/middle temporal cortex 
 Anterior cingulu 
 Posterior cingulum 
 Precuneus 
 Prefrontal cortex 
 Superior temporal cortex 
 Lateral parietal cortex 
 Lateral occipital cortex 
 Pericentral cortex 
 Medial occipital cortex 
 Lateral ventricles 
10.4. 
Intrinsic Connectivity Contrast (ICC) 
For resting state functional MRI, the outcome will be ICC. With this approach a map of 
the total connectivity of each voxel to all other voxels is computed. For ICC, a composite 
region of AD affected brain regions will be determined, including: prefrontal, lateral 
temporal, posterior cingulate/precuneus, anterior cingulate, lateral parietal, medial 
temporal, and lateral occipital regions.  
 
Individual exploratory regions include: 
 Hippocampus 
 Entorhinal cortex 
 Parahippocampal cortex 
 Amygdala 
 Fusiform gyrus 
 Lingual gyrus 
 Inferior/middle temporal cortex 
 Anterior cingulum 
 Posterior cingulum 
 Precuneus 
 Prefrontal cortex 
 Superior temporal cortex 
 Lateral parietal cortex 
 Lateral occipital cortex 
 Pericentral cortex 
 Medial occipital cortex 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 28 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
11. PHARMACOKINETIC/PHARMACODYNAMIC DATA 
11.1. 
Pharmacokinetic Sample Collection  
Blood samples for plasma concentration of CT1812 will be collected at: 
 Baseline V2 (Study Day 1)  
 V3 (Study Day 15) 
 V4 (Study Day 29) 
 V5 (Study Day 43) 
 V6 (Study Day 64) 
 V7 (Study Day 85) 
 V8 (Study Day 106) 
 V9 (Study Day 127) 
 V10 (Study Day 148) 
 Final/Early Discontinuation V11 (Study Day 169) (for subjects participating in the 
Primary Study Only) 
 V13 (Study Day 253) (for subjects participating in the Extension Study) 
 Final/Early Discontinuation V15 (Study Day 337) (for subjects participating in the 
Extension Study) 
CSF samples for concentration of CT1812 will be collected at: 
 V1 (Study Day -60 to -1)/Step 4 
 Final/Early Discontinuation V11 (Study Day 169) (for subjects participating in the 
Primary Study Only) 
 V11 (Study Day 169) (for subjects participating in the Extension Study) 
 Final/Early Discontinuation V15 (Study Day 337) (for subjects participating in the 
Extension Study) 
11.2. 
Pharmacokinetic Concentrations 
Plasma concentrations of CT1812 will be listed and plotted across collection days for 
each subject, and summarized with descriptive statistics by treatment group.  
Plasma concentrations of CT1812 that are less than the limit of quantification (LOQ) of 
the assay will be designated a value of zero for the summation of concentration-time data. 
Concentration data in listings will be presented to the same number of significant figures 
as provided by the analytical laboratory. Summary statistics will be displayed to the 
number of decimal places appropriate for the accuracy of the data.  
Individual and summary pre-dose concentrations will be plotted across collection days 
with the plasma concentration axis displayed on a linear scale and on a logarithmic scale. 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 29 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
CSF concentrations will be listed for each subject, and summarized with descriptive 
statistics by dose level / treatment group.   In addition, CSF and Plasma concentrations of 
CT1812 concentrations will be normalized on both a mg-dose and a mg/kg-dose basis to 
account for both dose and body weight.  CT1812 CSF and plasma concentration will be 
time matched and the CT1812 CSF/plasma concentration ratios will be determined and 
summarized using descriptive statistics. 
11.3. 
Pharmacokinetic Parameters 
No pharmacokinetic parameters will be determined in this study. 
11.4. 
Statistical Analysis of Pharmacokinetic Parameters 
No pharmacokinetic parameters will be analyzed in this study. 
11.5. 
Pharmacodynamic Endpoints 
CSF samples will also be used for the evaluation of the following biomarkers associated 
: 
 
 
 
 
 Tau 
 phospho-tau 
 neurogranin 
 Synaptotagmin 
 synpatosomal-associated protein-25 (SNAP25) 
 NFL 
 YKL-40 ELISA 
 neuronal pentraxin-1 
 neuronal pentraxin -2 
 neuronal pentraxin receptor 
 complexin-2 
 syntaxin-1b 
 sytaxin-7 
 gamma-synuclein 
 rab GDI alpha 
 Phosphatidylethanolamine-binding protein 1 
 AP-2 complex subunit beta 
 14-3-3 protein zeta/delta 
CSF concentrations will be listed and plotted across collection days for each subject.  
CSF concentrations less than the LOQ of the assay for pharmacodynamic analysis will be 
designated either a value of zero or of LOQ, as applicable, after clarification from the 
Sponsor. 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 30 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
11.6. 
Pharmacodynamic Analysis 
Pharmacodynamic endpoints of CSF will be summarized by treatment and timepoint, 
using descriptive statistics for the original measurements as well as the change from 
baseline for continuous endpoints. 
11.7. 
Statistical Analysis of Pharmacodynamic Parameters 
Change from baseline in pharmacodynamic endpoints of CSF will be analysed using the 
MMRM or ANCOVA model described in section 9.3. The analysis will be performed for 
time points up to and including the 6-month time point, and 12-month time point 
respectively.  
11.8. 
Changes from the Analysis Planned in the Protocol 
There are no changes from the planned analysis described in the protocol. 
12. DATA LISTINGS AND SUMMARY TABLES 
12.1. 
Interim/Preliminary Data Analysis 
No interim analyses are planned.  
12.2. 
Listings and Tables for Clinical Study Report 
The data listings and summary tables, and associated figures, planned to be generated 
from the study data are listed in Appendix 1 and Appendix 2, respectively. The 
numbering and titles may vary in the final presentation, depending on the amount of data 
to be presented.  
Listings, tables and figures will be provided to the Sponsor in a form suitable for 
inclusion as appendices to the Clinical Study Report, in RTF or PDF format. The layout 
will be landscape A4 size, with a margin of 1 inch. The default font for listings and tables 
will be Courier New 8 pt.  
In the summary tables other than those included in the main text of the report, special 
characters and formatting will not be used.  
Data in listings will be ordered by cohort, then subject, then date/time. Screen failed 
subjects will be identified in the listings. 
Data to be presented graphically includes: Concentration-time data for each subject, and 
mean concentration values at each nominal sampling time-point for plasma CT1812 
concentration. 
Mean values for total scores for cognitive and clinical outcomes (ADAS-Cog14, NTB, 
ADCS-ADL, MMSE, CDR-SB) will be presented graphically by treatment group over 
time. 
12.3. 
Data Transfer to the Study Sponsor 
At the conclusion of the study, Avance will provide the Sponsor with an electronic copy 
of the listings, tables and graphs. This may be provided by email or by upload, as 
determined by the Sponsor.  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 31 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Details of the statistical analyses will be retained in the Avance study file for reference. 
13. GENERAL CONSIDERATIONS FOR DATA MANAGEMENT AND ANALYSIS 
13.1. 
Analysis Packages 
SAS 9.4 or higher (SAS Institute Inc., Cary, NC, USA) will be used for generating data 
listings and summary tables and associated figures, and for performing statistical 
analysis. 
13.2. 
Electronic Data Management 
All listings, tables and figures for inclusion in the appendices of the clinical study report 
will be generated using SAS programs.  
A copy of final listings, tables and figures will be retained in the Avance internal study 
file. A tracking log will be maintained detailing the date and initials of the staff member 
responsible for generating each listing, table or figure, and the staff member conducting 
the quality control review. Any erroneous results identified during subsequent checking 
process will be corrected by update of the SAS program, and the document recreated and 
then re-checked. To ensure an accurate data trail is maintained, corrections to electronic 
documents will be included on the tracking log, detailing the correction along with the 
date of the new version as well as the initials of the staff member responsible for the 
change and the verifying staff member. If statistical analysis is repeated with a modified 
data set, the new data produced will be saved as a new file. 
13.3. 
Archiving 
At the conclusion of the study, the final listings, tables and figures will be archived along 
with the analysis data sets and QC documentation. Copies will be retained in the Avance 
study file for a minimum of 15 years, and in the Avance secure archives in accordance 
with Avance standard operating procedures. 
 
 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 32 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Appendix 1: Planned Data Listings 
The following listings and figures of individual subject data are planned to be generated for this 
study, however the numbering and titles may vary, depending on the amount of data to be 
presented: 
Listing/Figure # 
Listings/Figure Title 
Panel 
Subject Participation 
Listing 16.2.1.1 
Informed Consent 
IC 
Listing 16.2.1.2 
Inclusion and Exclusion Criteria 
IE 
Listing 16.2.1.3 
Screen Failure Information 
SCF 
Listing 16.2.1.4 
Study Completion / Discontinuation 
SCD 
Protocol Deviations 
Listing 16.2.2.1 
Protocol Deviations 
DV 
Listing 16.2.2.2 
Additional Comments 
CO 
Analysis Populations 
Listing 16.2.3.1 
Analysis Set Inclusion by Subject 
(derived) 
Demographics and Baseline Information 
Listing 16.2.4.1 
Demographics 
DM 
Listing 16.2.4.2 
Medical, Surgical and Psychiatric History 
MH 
Listing 16.2.4.3 
 
AD 
Listing 16.2.4.4 
Physical Examination at Screening 
PE 
Listing 16.2.4.5 
Serology Screening 
SER 
Listing 16.2.4.6 
Height and Weight at Screening 
HTWT 
Listing 16.2.4.7 
Blood sampling for Apolipoprotein E (ApoE) genotyping 
APOE 
Listing 16.2.4.8 
Modified Hachinski exam 
ACM 
Listing 16.2.4.9 
Geriatric Depression Score 
ACM 
Treatment Administration 
Listing 16.2.5.1 
Study Drug Administration 
EX 
Listing 16.2.5.2 
Pre-dose Eligibility Reviews 
EL 
Pharmacokinetic, Pharmacodynamic and Efficacy Data 
Listing 16.2.6.1 
Pharmacokinetic Blood Sampling and Plasma 
Concentrations 
PKB, 
Bioanalytical 
Figure 16.2.6.2 
Individual Plasma Concentrations Over Time (Linear) 
Bioanalytical 
Figure 16.2.6.3 
Individual Plasma Concentrations Over Time (Semi-log) 
Bioanalytical 
Listing 16.2.6.4 
Pharmacokinetic CSF Sampling and Concentrations 
CSF, 
Bioanalytical 
Listing 16.2.6.5 
CT1812 CSF/plasma concentration ratio 
Bioanalytical 
Listing 16.2.6.6 
Pharmacodynamic CSF Results 
Bioanalytical 
Figure 16.2.6.7 
Individual Pharmacodynamic CSF Results Over Time  
Bioanalytical 
Listing 16.2.6.8 
Brain Scan performed 
BI 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 33 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Listing/Figure # 
Listings/Figure Title 
Panel 
Listing 16.2.6.8 
Alzheimer's Disease Assessment Scale-Cognition 
Subscale (ADAS-Cog) 
ADAS 
Listing 16.2.6.9 
Neuropsychological Test Battery (NTB) 
NTB 
Listing 16.2.6.10 
Alzheimer's Disease Clinical Study  Activities of Daily 
Living (ADCS-ADL) 
ADL 
Listing 16.2.6.11 
Mini Mental State Exam (MMSE) 
MMSE, 
ACM 
Listing 16.2.6.12 
Clinical Dementia Rating Scale  Sum of the Boxes 
(CDR-SB) 
CDR 
Listing 16.2.6.13 
Alzheimer's Disease Clinical Study  Clinician Global 
Impression of Change (ADCS-CGIC) 
CGIC 
Listing 16.2.6.14 
Distribution Volume Ratio (DVR) 
Imaging 
Listing 16.2.6.15 
SUV ratio (SUVR) 
Imaging 
Listing 16.2.6.16 
Volumetric MRI 
Imaging 
Listing 16.2.6.17 
Intrinsic Connectivity Contrast (ICC) 
Imaging 
Safety Data (Adverse Events) 
Listing 16.2.7.1 
Adverse Events - CRF Data Only 
AE, SAE 
Listing 16.2.7.2 
Adverse Events - MedDRA Coding and Calculated 
Values 
AE, SAE 
Listing 16.2.7.3 
Prior and Concomitant Medications  CRF Data Only 
CM 
Listing 16.2.7.4 
Prior and Concomitant Medications  WHODrug Coding 
and Calculated Values 
CM 
Safety Data (Clinical Laboratory Evaluations) 
Listing 16.2.8.1 
Clinical Laboratory Blood Sample Collection 
LB 
Listing 16.2.8.2 
Hematology Results 
labdata 
Listing 16.2.8.3 
Clinical Chemistry Results 
labdata 
Listing 16.2.8.4 
Coagulation Results 
labdata 
Listing 16.2.8.5 
Thyroid Test Results 
labdata 
Listing 16.2.8.6 
Clinical Laboratory Urine Sample Collection 
LB 
Listing 16.2.8.7 
Urinalysis Results 
labdata 
Safety Data (Other Assessments) 
Listing 16.2.9.1 
Vital Signs 
VS 
Listing 16.2.9.2 
Vital Signs, Calculated Changes from Baseline 
VS 
Listing 16.2.9.3 
ECG Parameters 
EG 
Listing 16.2.9.4 
ECG Parameters, Calculated Changes from Baseline 
EG 
Listing 16.2.9.5 
Height and Weight 
HTWT 
Listing 16.2.9.6 
Physical Examinations Changes Over Time 
PE 
Listing 16.2.9.7 
Neurological Examination 
NE 
Listing 16.2.9.8 
Columbia Suicide Severity Rating Scale 
CSSRS 
 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 34 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
Appendix 2: Planned Summary Tables  
 
The following summary tables are planned to be produced, however the table numbers and 
titles may vary, depending on the amount of data to be presented: 
14.1 Subject Data Summaries  
 
Table 14.1.1 
Summary of Study Participation  
 
Table 14.1.2 
Summary of Demographics  
 
Table 14.1.3 
Summary of Treatment / Total Dose Administered  
 
14.2 Pharmacokinetic and/or Efficacy Data Summaries  
14.2.1 Pharmacokinetic Plasma Concentration Summaries  
 
Table 14.2.1.1 
Summary of Plasma Concentrations of CT1812 Over Time by 
Treatment 
 
Figure 14.2.1.2 Mean Plasma Concentrations of CT1812 Over Time by Treatment 
(Linear)  
 
Figure 14.2.1.3 Mean Plasma Concentrations of CT1812 Over Time by Treatment 
(Semi-log)  
 
Table 14.2.1.4 
Summary of Normalized Plasma Concentrations of CT1812 Over 
Time by Treatment 
14.2.2 Pharmacokinetic CSF Concentration Summaries  
 
Table 14.2.2.1 
Summary of CSF Concentrations Over Time by Treatment 
 
Table 14.2.2.2 
Summary of Normalized CSF Concentrations Over Time by 
Treatment 
 
Table 14.2.2.3 
CT1812 CSF/plasma concentration ratio  
14.2.3 Pharmacodynamic Data Summaries  
 
Table 14.2.3.1 
Summary of 
Disease by Treatment 
 
Figure 14.2.3.2 Mean Change from Baseline in CSF biomarkers associated with 
 Over Time by Treatment  
 
Table 14.2.3.3 
Analysis of Change from Baseline in CSF biomarkers associated 
, up to 6-months 
 
Figure 14.2.3.4 LS Mean Change from Baseline in CSF biomarkers associated 
Treatment, up to 6-
months  


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 35 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Table 14.2.3.5 
Analysis of Change from Baseline in CSF biomarkers associated 
, up to 12-months  
 
Figure 14.2.3.6 LS Mean Change from Baseline in CSF biomarkers associated 
by Treatment, up to 12-
months  
14.2.4 Efficacy Data Summaries  
 
Table 14.2.4.1 
Scale-Cognition Subscales (ADAS-Cog11, ADAS-Cog13, 
ADAS-Cog14) 
 
Table 14.2.4.2 
Summary of Total Score for Alzheimer's Disease Assessment 
Scale-Cognition Subscale (ADAS-Cog11) 
 
Figure 14.2.4.3 Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog11) 
Over Time 
 
Table 14.2.4.4 
Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog11), 
up to 6-months 
 
Figure 14.2.4.5 LS Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog11) 
Over Time, up to 6-months 
 
Table 14.2.4.6 
Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog11), 
up to 12-months 
 
Figure 14.2.4.7 LS Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog11) 
Over Time, up to 12-months 
 
Table 14.2.4.8 
Summary of Total Score for Alzheimer's Disease Assessment 
Scale-Cognition Subscale (ADAS-Cog13) 
 
Figure 14.2.4.9 Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog13) 
Over Time 
 
Table 14.2.4.10 Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog13), 
up to 6-months 
 
Figure 14.2.4.11 LS Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog13) 
Over Time, up to 6-months 
 
Table 14.2.4.12 Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog13), 
up to 12-months 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 36 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Figure 14.2.4.13 LS Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog13) 
Over Time, up to 12-months 
 
Table 14.2.4.14 Summary of Total Score for Alzheimer's Disease Assessment 
Scale-Cognition Subscale (ADAS-Cog14) 
 
Figure 14.2.4.15 Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog14) 
Over Time 
 
Table 14.2.4.16 Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog14), 
up to 6-months 
 
Figure 14.2.4.17 LS Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog14) 
Over Time, up to 6-months 
 
Table 14.2.4.18 Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog14), 
up to 12-months 
 
Figure 14.2.4.19 LS Mean Change from Baseline in Total Score for Alzheimer's 
Disease Assessment Scale-Cognition Subscale (ADAS-Cog14) 
Over Time, up to 12-months 
 
Table 14.2.4.20 Individual Trail Making times for Neuropsychological Test 
Battery (NTB)) 
 
Table 14.2.4.21 Summary of total completion time of Trail A and Trail B for 
Neuropsychological Test Battery (NTB)  
 
Figure 14.2.4.22 Mean Change from Baseline in total completion time of Trail A 
and Trail B for Neuropsychological Test Battery (NTB) Over 
Time 
 
Table 14.2.4.23 Analysis of total completion time of Trail A and Trail B for 
Neuropsychological Test Battery (NTB), up to 6-months  
 
Figure 14.2.4.24 LS Mean Change from Baseline in total completion time of Trail 
A and Trail B for Neuropsychological Test Battery (NTB) Over 
Time, up to 6-months 
 
Table 14.2.4.25 Analysis of total completion time of Trail A and Trail B for 
Neuropsychological Test Battery (NTB), up to 12-months  
 
Figure 14.2.4.26 LS Mean Change from Baseline in total completion time of Trail 
A and Trail B for Neuropsychological Test Battery (NTB) Over 
Time, up to 12-months 
 
Table 14.2.4.27 Individual Total 
 
Activities of Daily Living (ADCS-ADL) 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 37 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Table 14.2.4.28 Summary of Total Score for Alzheimer's Disease Clinical Study  
Activities of Daily Living (ADCS-ADL)  
 
Figure 14.2.4.29 Mean Change from Baseline in Total Score for Alzheimer's 
Disease Clinical Study  Activities of Daily Living (ADCS-ADL) 
Over Time 
 
Table 14.2.4.30 Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Clinical Study  Activities of Daily Living (ADCS-
ADL), up to 6-months  
 
Figure 14.2.4.31 
Disease Clinical Study  Activities of Daily Living (ADCS-ADL) 
Over Time, up to 6-months 
 
Table 14.2.4.32 Analysis of Change from Baseline in Total Score for Alzheimer's 
Disease Clinical Study  Activities of Daily Living (ADCS-
ADL), up to 12-months  
 
Figure 14.2.4.33 
Disease Clinical Study  Activities of Daily Living (ADCS-ADL) 
Over Time, up to 12-months 
 
Table 14.2.4.34 Individual Total Scores for Mini Mental State Exam (MMSE) 
 
Table 14.2.4.35 Summary of Total Score for Mini Mental State Exam (MMSE)  
 
Figure 14.2.4.36 Mean Change from Baseline in Total Score for Mini Mental State 
Exam (MMSE) Over Time 
 
Table 14.2.4.37 Analysis of Change from Baseline in Total Score for Mini Mental 
State Exam (MMSE), up to 6-months  
 
Figure 14.2.4.38 LS Mean Change from Baseline in Total Score for Mini Mental 
State Exam (MMSE) Over Time, up to 6-months 
 
Table 14.2.4.39 Analysis of Change from Baseline in Total Score for Mini Mental 
State Exam (MMSE), up to 12-months  
 
Figure 14.2.4.40 LS Mean Change from Baseline in Total Score for Mini Mental 
State Exam (MMSE) Over Time, up to 12-months 
 
Table 14.2.4.41 Individual Total Scores for Clinical Dementia Rating Scale  Sum 
of the Boxes (CDR-SB) 
 
Table 14.2.4.42 Summary of Total Score for Clinical Dementia Rating Scale  
Sum of the Boxes (CDR-SB) 
 
Figure 14.2.4.43 Mean Change from Baseline in Total Score for Clinical Dementia 
Rating Scale  Sum of the Boxes (CDR-SB) Over Time 
 
Table 14.2.4.44 Analysis of Change from Baseline in Total Score for Clinical 
Dementia Rating Scale  Sum of the Boxes (CDR-SB), up to 6-
months 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 38 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Figure 14.2.4.45 LS Mean Change from Baseline in Total Score for Clinical 
Dementia Rating Scale  Sum of the Boxes (CDR-SB) Over 
Time, up to 6-months 
 
Table 14.2.4.46 Analysis of Change from Baseline in Total Score for Clinical 
Dementia Rating Scale  Sum of the Boxes (CDR-SB), up to 12-
months 
 
Figure 14.2.4.47 LS Mean Change from Baseline in Total Score for Clinical 
Dementia Rating Scale  Sum of the Boxes (CDR-SB) Over 
Time, up to 12-months 
 
Table 14.2.4.48 Summary of Alzheimer's Disease Clinical Study  Clinician 
Global Impression of Change (ADCS-CGIC) 
 
Table 14.2.4.49 Analysis of Alzheimer's Disease Clinical Study  Clinician 
Global Impression of Change (ADCS-CGIC), up to 6-months 
 
Table 14.2.4.50 Analysis of Alzheimer's Disease Clinical Study  Clinician 
Global Impression of Change (ADCS-CGIC), up to 12-months 
 
Table 14.2.4.51 Frequency table for Alzheimer's Disease Clinical Study  
Clinician Global Impression of Change (ADCS-CGIC) 
 
Table 14.2.4.52 Individual Scores for Composite z-score scales (Cognitive, NTB, 
Memory, Attention, Executive Function) 
 
Table 14.2.4.53 Summary of Scores for Composite z-score scales (Cognitive, 
NTB, Memory, Attention, Executive Function)  
 
Figure 14.2.4.54 Mean Change from Baseline in Scores for Composite z-score 
scales (Cognitive, NTB, Memory, Attention, Executive Function) 
Over Time 
 
Table 14.2.4.55 Analysis of Change from Baseline in Scores for Composite z-
score scales (Cognitive, NTB, Memory, Attention, Executive 
Function), up to 6-months  
 
Figure 14.2.4.56 LS Mean Change from Baseline in Scores for Composite z-score 
scales (Cognitive, NTB, Memory, Attention, Executive Function) 
Over Time, up to 6-months 
 
Table 14.2.4.57 Analysis of Change from Baseline in Scores for Composite z-
score scales (Cognitive, NTB, Memory, Attention, Executive 
Function), up to 12-months  
 
Figure 14.2.4.58 LS Mean Change from Baseline in Scores for Composite z-score 
scales (Cognitive, NTB, Memory, Attention, Executive Function) 
Over Time, up to 12-months 
 
Table 14.2.4.59 Correlation between CSF Biomarkers and Efficacy Scales at 
Baseline 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 39 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Table 14.2.4.60 Correlation between change from baseline in CSF Biomarkers 
and change from baseline in Efficacy Scales  
14.2.5 Imaging Outcome Summaries  
 
Table 14.2.5.1 
Summary of Distribution Volume Ratio (DVR)  
 
Table 14.2.5.2 
Analysis of Change from Baseline in DVR: Composite region 
(pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.3 
Analysis of Change from Baseline in DVR: Exploratory regions 
(pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.4 
Analysis of Change from Baseline in DVR: Composite region 
(pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.5 
Analysis of Change from Baseline in DVR: Exploratory regions 
(pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.6 
Summary of SUV Ratio (SUVR)  
 
Table 14.2.5.7 
Analysis of Change from Baseline in SUVR: Composite region 
(pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.8 
Analysis of Change from Baseline in SUVR: Exploratory regions 
(pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.9 
Analysis of Change from Baseline in SUVR: Composite region 
(pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.10 Analysis of Change from Baseline in SUVR: Exploratory regions 
(pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.11 Summary of Volumetric MRI  
 
Table 14.2.5.12 Analysis of Change from Baseline in Volumetric MRI: 
Composite region (pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.13 Analysis of Change from Baseline in Volumetric MRI: 
Exploratory regions (pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.14 Analysis of Change from Baseline in Volumetric MRI: 
Composite region (pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.15 Analysis of Change from Baseline in Volumetric MRI: 
Exploratory regions (pooled analysis and by arm), up to 12-
months 
 
Table 14.2.5.16 Summary of Intrinsic Connectivity Contrast (ICC)  
 
Table 14.2.5.17 Analysis of Change from Baseline in ICC: Composite region 
(pooled analysis and by arm), up to 6-months 
 
Table 14.2.5.18 Analysis of Change from Baseline in ICC: Exploratory regions 
(pooled analysis and by arm), up to 6-months 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 40 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Table 14.2.5.19 Analysis of Change from Baseline in ICC: Composite region 
(pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.20 Analysis of Change from Baseline in ICC: Exploratory regions 
(pooled analysis and by arm), up to 12-months 
 
Table 14.2.5.21 Correlation between CSF Biomarkers and Imaging endpoints at 
Baseline 
 
Table 14.2.5.22 Correlation between change from baseline in CSF Biomarkers 
and change from baseline in Imaging endpoints  
 
Table 14.2.5.23 Correlation between Efficacy Scales and Imaging endpoints at 
Baseline 
 
Table 14.2.5.24 Correlation between change from baseline in Efficacy Scales and 
change from baseline in Imaging endpoints 
14.3 Safety Data Summaries  
14.3.1 Adverse Event Summaries 
 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events by 
Treatment 
 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Term and Treatment 
 
Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by Intensity 
(Severity) and Treatment 
 
Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by 
Relationship and Treatment 
 
Table 14.3.1.5 
Summary of Treatment-Emergent Adverse Events of at least 
Moderate Intensity and Related to Study Treatment, by Treatment 
14.3.2 Deaths, Other Serious and Significant Adverse Events  
 
Table 14.3.2.1 
Subjects with Serious Adverse Events 
 
Table 14.3.2.2 
Subjects with Adverse Events Leading to Study Withdrawal 
 
Table 14.3.2.3 
Subjects Who Died During the Study 
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse 
Event  
<Narratives by Subject, to be provided by Safety Officer> 
14.3.4 Clinical Laboratory Assessments  
 
Table 14.3.4.1 
Summary of Hematology Results by Treatment 
 
Table 14.3.4.2 
Summary of Clinical Chemistry Results by Treatment 
 
Table 14.3.4.3 
Summary of Coagulation Results by Treatment 


 
Statistical Analysis Plan
Final 1.0, 11 Mar 2021
Protocol No.: COG0105
Sponsor: Cognition Therapeutics, Inc.
 
CONFIDENTIAL 
S-DM-010 Appendix 1, T-DM-012v01 
Page 41 of 41 
Avance Clinical use only 
Effective Date: 29 Apr 2019 
 
 
Table 14.3.4.4 
Summary of Assessments of Hematology Results by Treatment 
 
Table 14.3.4.5 
Summary of Assessments of Clinical Chemistry Results by 
Treatment 
 
Table 14.3.4.6 
Summary of Assessments of Coagulation Results by Treatment 
 
Table 14.3.4.7 
Summary of Assessments of Urinalysis Results by Treatment 
 
Table 14.3.4.8 
Individual Subject Profiles for Clinical Laboratory Parameters 
With at Least One Clinically Significant Result 
14.3.5 Vital Signs  
 
Table 14.3.5.1 
Summary of Vital Signs (Pulse Rate) by Treatment 
 
Table 14.3.5.2 
Summary of Vital Signs (Systolic Blood Pressure) by Treatment 
 
Table 14.3.5.3 
Summary of Vital Signs (Diastolic Blood Pressure) by Treatment 
 
Table 14.3.5.4 
Summary of Vital Signs (Respiratory Rate) by Treatment 
 
Table 14.3.5.5 
Summary of Vital Signs (Temperature) by Treatment 
 
Table 14.3.5.6 
Summary of Vital Signs (Body weight) by Treatment 
14.3.6 ECG Parameters  
 
Table 14.3.6.1 
Summary of ECG Parameters (Ventricular Rate) by Treatment 
 
Table 14.3.6.2 
Summary of ECG Parameters (PR Interval) by Treatment 
 
Table 14.3.6.3 
Summary of ECG Parameters (QRS Duration) by Treatment 
 
Table 14.3.6.4 
Summary of ECG Parameters (QT Interval) by Treatment 
 
Table 14.3.6.5 
Summary of ECG Parameters (QTcF) by Treatment 
 
Table 14.2.6.6 
Summary of ECG Parameters (QTcB) by Treatment 
 
Table 14.3.6.7 
Summary of Derived Categorical QTcB by Treatment 

Prot_001.pdf: