Clinical trial NCT03249103
Conditions: Fibromyalgia
Keywords: Fibromyalgia
Sponsor: Aptinyx
Start date: 2017-08-14; Completion date: 2019-04-18
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to determine whether daily dosing with NYX-2925 changes markers of central pain processing in subjects with fibromyalgia by evaluating changes in evoked pain, and visual stimulation, functional magnetic resonance imaging (fMRI), resting state function connectivity magnetic resonance imaging (rs-fcMRI) and proton magnetic resonance spectroscopy (H-MRS) in fibromyalgia subjects on active drug versus placebo.

Detailed description:
This is a single-blind, exploratory, placebo-controlled, pilot study to assess the efficacy and safety of daily oral NYX-2925 in fibromyalgia subjects. The study will include a screening period (up to 30 days), a placebo period, an active treatment period with, and a follow-up period as follows:

* Placebo PO Every Day (QD) for 2 weeks
* NYX-2925 PO QD for 2 weeks (2x)
* Follow-up for 1 week

Eligible subjects will receive MRIs during the screening period, during the placebo period, during the NYX-2925 PO QD period. Safety assessments will be conducted and adverse events will be collected during the study. Daily pain scores and other fibromyalgia scales will be collected during the study. Daily pain scores and other fibromyalgia scales will be collected for exploratory analysis. During the follow-up period, an optional MRI will be completed for consenting subjects in order to evaluate duration of effect.

Arms: arm 1: Up to 24 subjects will receive placebo, NYX-2925 20 mg QD, and NYX-2925 200 mg QD for sequential 2 week treatment periods, then go into Follow-up for 1 week.
Interventions: intervention 1: NYX-2925 intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: NYX-2925 is a novel small molecule that modulates the N-methyl-D-aspartate receptor (NMDAR). intervention 2: Matching placebo capsules.

Protocol documents:
Prot_000.pdf: 
NCT03249103 
NYX-2925-2002 
A Phase 2, Single-Blind, Exploratory, Placebo-controlled, Pilot Study to Assess the 
Efficacy and Safety of Daily Oral NYX-2925 in Subjects With Fibromyalgia  
Protocol 
March 7, 2018 









































































































































SAP_001.pdf: 
NCT03249103 
NYX-2925-2002 
A Phase 2, Single-Blind, Exploratory, Placebo-controlled, Pilot Study to Assess the 
Efficacy and Safety of Daily Oral NYX-2925 in Subjects With Fibromyalgia  
SAP 
November 26, 2018 


 
Statistical Analysis Plan 
A Phase 2, Single-Blind, Exploratory, Placebo-controlled, 
Pilot Study to Assess the Efficacy and Safety of Daily Oral 
NYX-2925 in Subjects with Fibromyalgia 
 
Sponsor: 
 
Aptinyx Inc. 
 
 
Clinical Protocol No.:  
NYX-2925-2002 
Study Phase:  
2 
Investigational Product:  
NYX-2925 
Prepared by: 
 
 
Date:  
November 26, 2018 
SAP Version:  
Final Version 1.0 
Protocol Version:  
 
 
Confidential and Proprietary Information 




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Table of Contents 
 
1. 
List of Abbreviations and Special Terms .............................................................................................. 6 
2. 
Introduction ........................................................................................................................................... 9 
3. 
Study Objectives ................................................................................................................................. 10 
3.1 
Primary Objective ....................................................................................................................... 10 
3.2 
Secondary Objective ................................................................................................................... 10 
3.3 
Exploratory Analyses .................................................................................................................. 10 
4. 
Study Overview .................................................................................................................................. 11 
4.1 
Study Design and Study Drug Treatment Periods ...................................................................... 11 
4.2 
Subject Randomization ............................................................................................................... 11 
4.3 
Number of Subjects ..................................................................................................................... 11 
4.4 
Sample Size Considerations ........................................................................................................ 11 
4.5 
Unblinding Study Drug Treatment Procedures ........................................................................... 11 
4.6 
Analyses Changes from the Protocol .......................................................................................... 11 
5. 
General Statistical Principles .............................................................................................................. 11 
5.1 
Key Definitions ........................................................................................................................... 11 
5.1.1 Day 1/Date of First Dose ............................................................................................................ 11 
5.1.2 Study Day.................................................................................................................................... 12 
5.1.3 Not Reported ............................................................................................................................... 12 
5.1.4 Baseline and Post-Baseline Values ............................................................................................. 12 
5.1.5 Change from Baseline ................................................................................................................. 12 
5.1.6 Change from Treatment Periods ................................................................................................. 12 
5.1.7 Percent Change from Baseline .................................................................................................... 13 
5.2 
Treatment Allocation .................................................................................................................. 13 
5.3 
Treatment Group Comparisons ................................................................................................... 13 
5.4 
Conventions ................................................................................................................................ 14 
5.4.1 Descriptive Statistics ................................................................................................................... 14 
5.4.2 Frequency Distributions .............................................................................................................. 14 
5.4.3 Safety Data Statistical Inference ................................................................................................. 14 
5.4.4 Efficacy and Pharmacodynamic Data Statistical Inference ........................................................ 14 
5.4.4.1 
P-values and Type I Error ....................................................................................................... 14 
5.4.4.2 
Paired t-test and Wilcoxon Signed-Rank Test ........................................................................ 15 
5.4.4.3 
Frequency Distribution Tests .................................................................................................. 15 
5.5 
Analysis Visits ............................................................................................................................ 15 


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5.5.1 Safety and Efficacy Analysis Visits ............................................................................................ 16 
5.5.2 Daily Numeric Pain Rating Scores Analysis Visits .................................................................... 17 
5.6 
Data Imputations ......................................................................................................................... 17 
5.6.1 Character Values in Numeric Data ............................................................................................. 18 
5.6.2 Missing Analysis Values ............................................................................................................. 18 
5.6.3 Missing or Partial Dates .............................................................................................................. 18 
5.7 
Multiplicity Adjustments ............................................................................................................ 19 
5.8 
By-Center Analyses .................................................................................................................... 19 
5.9 
Subpopulation Analyses .............................................................................................................. 19 
6. 
Analysis Populations ........................................................................................................................... 19 
6.1 
Safety Population ........................................................................................................................ 19 
6.2 
Efficacy Population ..................................................................................................................... 19 
6.3 
PP Population .............................................................................................................................. 20 
7. 
Disposition, Baseline, and Other Characteristics ................................................................................ 20 
7.1 Subject Disposition ............................................................................................................................. 20 
7.2 Demographics and Disease History .................................................................................................... 21 
7.3 Subject Inclusion and Exclusion Criteria ............................................................................................ 21 
7.4 Medical History .................................................................................................................................. 21 
8. 
Study Drug Exposure and Other Medications .................................................................................... 21 
8.1 
Study Drug Accountability ......................................................................................................... 21 
8.2 
Study Drug Exposure .................................................................................................................. 23 
8.3 
Prior and Concomitant Medications ........................................................................................... 23 
9. 
Pharmacodynamic Analyses ............................................................................................................... 24 
9.1 
Neuroimaging Analyses Overview ............................................................................................. 24 
9.1.1 Primary Pharmacodynamic Endpoint ......................................................................................... 24 
9.1.2 Primary Pharmacodynamic Endpoint Analysis .......................................................................... 24 
9.1.2.1 
Functional Connectivity Magnetic Resonance Imaging (fcMRI) ........................................... 24 
9.1.2.2 
Evoked Pain and Visual Stimulation....................................................................................... 25 
9.1.2.3 
Proton Magnetic Resonance Spectroscopy (1H-MRS) ............................................................ 26 
9.2 
Secondary Pharmacodynamic Data and Endpoints ..................................................................... 26 
10. Exploratory Efficacy Analyses ........................................................................................................... 26 
10.1 
Multi-Modal Automated Sensory Testing (MAST) Pressure Pain Sensitivity, Algometry, Cuff 
Algometry, and Visual Stimulation Task ................................................................................................ 26 
10.2 
Numeric Pain Rating Scale (NPRS) Score Assessing Average Pain Intensity in the Past 24 
Hours 27 


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10.3 
Numeric Pain Rating Scale (NPRS) Score Assessing Worst Pain Intensity in the Past 24 Hours
 
28 
10.4 
Brief Pain Inventory (BPI) - Short Form .................................................................................... 28 
10.5 
PROMISFM Fatigue Profile ......................................................................................................... 29 
10.6 
Multidimensional Inventory of Subject Cognitive Impairment (MISCI) ................................... 31 
10.7 
Revised Fibromyalgia Impact Questionnaire (FIQR) ................................................................. 32 
10.8 
PROMIS Sleep Disturbance - Short Form .................................................................................. 33 
10.9 
Hospital Anxiety and Depression Scale (HADS) ....................................................................... 34 
10.10 
PROMIS Physical Function - Short Form .............................................................................. 34 
10.11 
Patient Global Impression of Change (PGI-C) ....................................................................... 36 
10.12 
2011 American College of Rheumatology Fibromyalgia Criteria .......................................... 37 
11. Summary of Pharmacodynamic and Efficacy Analyses ..................................................................... 38 
12. Safety Analyses ................................................................................................................................... 38 
12.1 
Adverse Events ........................................................................................................................... 38 
12.2 
Clinical Laboratory Tests ............................................................................................................ 40 
12.3 
Vital Sign Measurements ............................................................................................................ 42 
12.4 
12-Lead Electrocardiogram (ECG) ............................................................................................. 42 
12.5 
Physical Examinations ................................................................................................................ 43 
12.6 
Other Safety Analyses ................................................................................................................. 43 
12.6.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................................... 43 
12.6.2 
Body Weight ........................................................................................................................... 44 
12.6.3 
Other Reportable Events ......................................................................................................... 44 
13. Other Analyses .................................................................................................................................... 44 
13.1 Protocol Deviations ............................................................................................................................. 44 
14. Interim Analyses ................................................................................................................................. 45 
15. Planned CSR Tables, Figures, and Listings in Section 14 .................................................................. 45 
16. Planned CSR Appendices in Section 16.2 .......................................................................................... 51 
17. References ........................................................................................................................................... 53 
Appendix I: Schedule of Assessments ........................................................................................................ 57 
 
 
 
 


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1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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November 26, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. Introduction 
This statistical analysis plan (SAP) describes the planned statistical analysis and reporting of the 
clinical study protocol titled “A Phase 2, Single-Blind, Exploratory, Placebo-controlled, Pilot Study 
to Assess the Efficacy and Safety of Daily Oral NYX-2925 in Subjects with Fibromyalgia” dated on 
March 7, 2018, amendment #3.   
The structure and content of this SAP provides sufficient detail to meet the requirements identified by 
the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and International 
Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals 
for Human Use: Guidance on Statistical Principles in Clinical Trials[1].  All work planned and 
reported for this SAP will follow internationally accepted guidelines, published by the American 
Statistical Association[2] and the Royal Statistical Society[3], for statistical practice.   
The purposes of this SAP are to: 
• 
Outline the types of analyses and presentations of data that will form the basis for drawing 
conclusions to the study objectives and hypotheses outlined in the protocol 
• 
Explain in detail how the data will be handled and analyzed, adhering to commonly accepted 
standards and practices for Good Statistical Practice 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to performing any interim analyses.  The planned analyses identified in this SAP may be 
included in clinical study reports (CSR), regulatory submissions, or future manuscripts.  Also, post-
hoc exploratory analyses not identified in this SAP may be performed to further examine study data.  
Any post-hoc or unplanned exploratory analyses performed will be clearly identified as such in the 
final CSR. 
The following documents were reviewed in preparation of this SAP: 
• 
 
 
• 
 
 
 
• 
 


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• 
 
 
 
 
 
• 
 
The reader of this SAP is encouraged to also read the clinical study protocol and other identified 
documents for details on the planned conduct of this study.  Operational aspects related to collection 
and timing of planned clinical assessments are not repeated in this SAP unless relevant to the planned 
analyses. 
3. Study Objectives 
3.1 Primary Objective 
The primary objective of this study is to determine whether daily dosing with NYX-2925 20 or 200 
mg changes the markers of central pain processing in subjects with fibromyalgia using functional 
magnetic resonance imaging (fMRI), resting state functional connectivity magnetic resonance 
imaging (rs-fcMRI) and proton magnetic resonance spectroscopy (1H-MRS) on active drug versus 
placebo. 
 
nd 
ain 
3
3


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4. Study Overview 
4.1 Study Design and Study Drug Treatment Periods 
This is a single-blind, exploratory, placebo-controlled, pilot study to assess the efficacy and safety of 
daily oral NYX-2925 in fibromyalgia subjects.  The study includes a screening period (up to 30 days), 
a placebo period, an active treatment period with 2 dose strengths, and a follow-up period as follows: 
• 
Placebo PO QD for 2 weeks 
• 
NYX-2925 20 mg PO QD for 2 weeks 
• 
NYX-2925 200 mg PO QD for 2 weeks 
• 
Follow-up for 1 week 
The schedule of assessments is provided in in Appendix I. 
4.2 Subject Randomization 
This study does not require a randomization because the treatment periods are fixed. 
4.3 Number of Subjects 
The protocol for this study planned on enrolling approximately 24 subjects at 2 study sites in the 
United States. 
4.4 Sample Size Considerations 
The sample size for this pilot study was based on practical, clinical considerations rather than a 
formal determination of statistical power. 
4.5 Unblinding Study Drug Treatment Procedures 
Not applicable because this is not a double-blind or randomized study.  
4.6 Analyses Changes from the Protocol 
In Section 12.6.1 of the protocol, it states that TEAE summaries will be provided separately for each 
study period and the follow-up period.  TEAEs will be summarized and grouped based on the last 
study drug treatment the subject received compared to the start date of the event explained in Section 
5.2.  The rest of the analyses stated in the protocol support the analyses planned in this SAP. 
5. General Statistical Principles 
5.1 Key Definitions 
The following items below are standard terminologies discussed throughout the SAP. 
5.1.1 Day 1/Date of First Dose 
The date of first dosing of study drug is not collected on the CRF because subjects are given study 
drug to administer themselves.  Since both compliance and missed doses were captured, it will be 
assumed that Day 1 is the same day as the first dosing day of study drug for subjects in the safety 
population later described in the SAP in Section 6.1. 


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5.1.2 Study Day 
Study day will be calculated in reference to Day 1 stated above in Section 5.1.1.  For assessments 
conducted on or after the Day 1 date, study day is calculated as the assessment date – Day 1 date + 1.  
For assessments conducted before the Day 1 date, study day is calculated as the assessment date – 
Day 1 date.  There is no Study Day 0 in this study. 
5.1.3 Not Reported 
A not reported value may be displayed in a listing, summary statistics table, frequency table, shift 
table, etc.  The not reported record could be due to a missed sample/measurement/assessment, missed 
visit, unable to calculate a value, or withdrawal from the study early. 
5.1.4 Baseline and Post-Baseline Values 
Unless otherwise specified, the baseline value is defined as the last measurement/assessment 
collected/derived on Day 1 or during screening.  Unless otherwise specified, post-baseline values are 
defined as collected/derived measurements/assessments after Day 1. 
For specific questionnaire assessments, missing responses on Day 1 will not be substituted for 
screening values for the baseline specific questionnaires.  If the total score cannot be calculated at 
Day 1, then the screening visit will be used if the total score can be calculated at screening.  If the 
total score cannot be calculated for both screening and Day 1 visits, then the latest individual values 
and subscale scores will be used for the baseline.  All questions within a specific questionnaire will be 
paired together in an analysis visit for the baseline records. 
5.1.5 Change from Baseline 
If both post-baseline and baseline values are present/imputed, then change from baseline is defined as 
each post-baseline value – baseline value.  Otherwise the change from baseline will not be reported. 
5.1.6 Change from Treatment Periods 
If both post-values and pre-values are present/imputed then change from treatment periods are 
defined as the following: 
• 
Change from Week 2 (Placebo) 
o Post-values conducted at Weeks 3, 4, 5, 6, and Follow-up (Week 7) 
o Pre-value is defined as the last measurement/assessment collected/derived on Week 
2 (end of the Placebo Period) 
• 
Change from Week 4 (NYX-2925 20 mg PO QD) 
o Post-values conducted at Week 5, Week 6, and Follow-up (Week 7) 
o Pre-value is defined as the last measurement/assessment collected/derived on Week 
4 (end of the NYX-2925 20 mg PO QD Period) 
• 
Change from Week 6 (NYX-2925 200 mg PO QD) 
o Post-values conducted at Follow-up (Week 7) 
o Pre-value is defined as the last measurement/assessment collected/derived on Week 
6 (end of the NYX-2925 200 mg PO QD Period) 
Otherwise the change from treatment periods will not be reported. 


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5.1.7 Percent Change from Baseline 
If the baseline value is not equal to zero or missing and the change from baseline value is 
present/imputed, then the percent change from baseline is defined as 100 x (change from baseline / 
baseline) and is rounded off to 1 number after the decimal point.  Otherwise the percent change from 
baseline will not be reported. 
5.2 Treatment Allocation 
Subjects are planned to receive multiple study drug treatments in the study.  Therefore, the following 
treatments will be assigned during these periods: 
• 
Screening Visit until 1 Day Prior to the Day 1 (Baseline) Visit:  No Treatment 
• 
Day 1 (Baseline) Visit until the Week 2 Visit:  
 
• 
1 Day After Week 2 Visit until the Week 4 Visit:  
 
o If any adverse events and/or concomitant medications start on the Week 2 visit, then 
those records will be assigned to the 
 treatment arm. 
• 
1 Day After Week 4 Visit until the Week 6 Visit: 
 
o If any adverse events and/or concomitant medications start on the Week 4 visit, then 
those records will be assigned to the 
 treatment arm. 
• 
1 Day After Week 6 Visit until the Follow-Up (Week 7) Visit:  
 
• 
Unscheduled or Early Termination Visits:  Last Study Drug Dispensed and Taken 
5.3 Treatment Group Comparisons 
The following treatment groups will be summarized in the statistical tables: 
• 
Placebo 
• 
NYX-2925 20 mg PO QD 
• 
NYX-2925 200 mg PO QD 
• 
All Doses of NYX-2925 
o Pooled for adverse events, concomitant medications, and study drug treatment 
compliance and exposure tables. 
• 
Not Treated 
o This will only be displayed for the analysis population table that presents subjects 
screened, but were not enrolled in the study or dispensed study drug. 
• 
All Subjects 
o This will only be displayed for the analysis population and concomitant medications 
tables. 
The following changes in treatment period comparisons will be performed for efficacy: 
• 
Change from Baseline 
• 
Change from Week 2 
 
• 
Change from Week 4 
 
• 
Change from Week 6 
 


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5.4 Conventions 
 
 
 
 
 
 
 
 
 
 
 
5.4.1 Descriptive Statistics 
Descriptive statistics (the number of subjects [n], mean, standard deviation [SD], median, minimum, 
maximum, and not reported) will be used to summarize continuous variables.  Means will be 
presented to one more decimal place than the recorded data.  Medians will be presented using the 
same number of decimal places as the recorded data unless the calculated median results in an 
additional decimal place ending in “5” (i.e. 5 & 7 = 6, 5 & 8 = 6.5, etc.).  Standard deviations will be 
presented to two more decimal places than the recorded data.  Minimum and maximum values will be 
presented using the same number of decimal places as the recorded data. 
For data reporting 3 or more numbers after the decimal point (i.e. urinalysis specific gravity), the 
descriptive statistics for mean, standard deviation, median, minimum, and maximum will all be 
reported to the same precision as the data was collected.  For data reporting 2 numbers after the 
decimal point, the descriptive statistics for standard deviation will be reported as 3 numbers after the 
decimal place (same as the mean). 
5.4.2 Frequency Distributions 
Frequency distributions (count [n], percentage of subjects [%], and not reported) will be used to 
summarize categorical or qualitative variables.  In general, the denominator for the percentage 
calculation will be based upon the total number of subjects in the study population for the treatment 
groups for that particular time point assessment.  Records that are missing or not done will be 
displayed as “Not Reported” and will not be factored into the percentage calculation, unless otherwise 
specified.  Percentages will be presented to a maximum of one number after the decimal place. 
5.4.3 Safety Data Statistical Inference 
All safety data summaries will use descriptive statistics, frequency distributions, and/or shift tables.  
No formal statistical testing will be performed with the safety data. 
5.4.4 Efficacy and Pharmacodynamic Data Statistical Inference 
5.4.4.1 P-values and Type I Error 
P-values will be reported out and rounded off to 4 numbers after the decimal point (i.e. “0.####).  
Any p-values that are > 0.9999 will be reported as “>.9999” in the tables.  Any p-values that are < 
0.0001 will be reported as “<.0001” in the tables.  Unless otherwise specified, p-values will be tested 
using alpha at the 0.05 level.  This pilot study is not formally powered to test any specific hypothesis; 
and, that should be taken into consideration for all statistical conclusions. 


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5.4.4.2 Paired t-test and Wilcoxon Signed-Rank Test 
Testing for differences between treatment periods will be performed by using a 2-sided paired t-test, 
comparing pre and post values based on the analysis visits collected for particular pharmacodynamic 
and efficacy data stated in Sections 9 and 10.  The null hypothesis will be defined as the mean change 
from pre and post values is 0.  Both the pre and post values must be non-missing in order to be 
included in the paired t-test comparison.  Here is the SAS® code: 
PROC TTEST DATA=ADAM; 
 
/* where CHG# is the specific post-value – pre-value of interest */ 
 
VAR CHG#; 
RUN; 
Additionally, the nonparametric Wilcoxon signed-rank test will be provided along with the 2-sided 
paired t-test.  The null hypothesis will be defined as the median change from pre and post values is 0.  
Both the pre and post values must be non-missing in order to be included in the statistical 
comparison.  Here is the SAS® code: 
PROC UNIVARIATE DATA=ADAM; 
 
/* where CHG# is the specific post-value – pre-value of interest */ 
 
VAR CHG#; 
RUN; 
5.4.4.3 Frequency Distribution Tests 
Frequency distributions that have two responses (i.e. yes/no) and compare two different treatment 
periods (i.e. NYX-2925 20 mg PO QD versus placebo) will use McNemar’s exact test for reporting a 
p-value.  This is referred to as a 2x2 table for dependent categorical data.  Subjects will need to have 
both treatment period values as non-missing for the comparison.  The 2x2 table must have less than 2 
non-missing levels or the p-value will be considered non-calculable.  Here is the SAS® code: 
PROC FREQ DATA=ADAM; 
 
WEIGHT COUNT; 
 
/* where BEFORE and AFTER represent the 2 different treatment periods comparison */ 
 
TABLES BEORE*AFTER / AGREE; 
 
EXACT MCNEM; 
 
ODS OUTPUT MCNEMARSTEST=MCNEMARSTEST; 
RUN; 
5.5 Analysis Visits 
Analysis visits are determined based on the collected/derived data for the study that will be used for 
listings and statistical analyses.  In some events, there may be differences in visits depending on the 
data used for statistical summaries and as a result analysis visits are defined.  For example, data for 


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efficacy versus safety may have different methods for defining the analysis visits.  The subsections 
below represent the analysis visits that will be used to support the analyses in this SAP. 
In the event more than one record is collected/derived within an analysis visit, the non-missing record 
with the date closest to the target day will be selected.  If there is a tie between two dates between the 
target date, then the first date will be used.  If more than one non-missing record occurs on the same 
date, then the first planned scheduled result will be used. 
Clinical laboratory tests will also consider lowest, highest, and most abnormal post-baseline results as 
additional analyses.  More details are provided in Section 12.2. 
5.5.1 Safety and Efficacy Analysis Visits 
Each safety analyses section will state which analysis visits will be used in their respective summary 
tables.  All collected/derived records will be included in the appendix listings. 
Protocol/CRF Term 
Analysis Visit (Target Day) 
Study Day Window 
Screening 
Screening (-30) 
≤ Day -1 
Day 1/Baseline 
Day 1 (1) 
Only Day 1 
N/A 
Baseline(a) (N/A) 
≤ Day 1 
N/A 
Unscheduled Week 1 (N/A) 
Day 2 to Day 3 
Week 1 
Week 1 (7) 
Day 4 to Day 10 
Week 2 
Week 2 (14) 
Day 11 to Day 17 
Week 3 
Week 3 (21) 
Day 18 to Day 24 
Week 4 
Week 4 (28) 
Day 25 to Day 31 
Week 5 
Week 5 (35) 
Day 32 to Day 38 
Week 6 
Week 6 (42) 
Day 39 to Day 45 
Follow-Up/Week 7 
Early Termination(b) (N/A) 
Day 2 or Later 
Follow-Up/Week 7 
Follow-Up (Week 7)(c) (49) 
Day 46 to Day 56 
N/A 
Unscheduled Late Follow-Up(d) (Week 7) (N/A) 
Day 57 or Later 
N/A 
Repeat Follow-Up(e) (N/A) 
Any Repeat Follow-
Up Visits 
N/A 
Last Post-NYX-2925 Visit(f) (N/A) 
Week 3 Visit + 1 
Day or Later 
N/A 
Any Post-NYX-2925 Visit(g) (N/A) 
Week 3 Visit + 1 
Day or Later 
N/A 
Overall Post-NYX-2925 Visits(h) (N/A) 
Week 3 Visit + 1 
Day or Later 
(a) Baseline definition described in Section 5.1.4. 


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(b) The Early Termination visit will only be included in summary tables for last and overall post-
NYX-2925 visits if study drug of NYX-2925 was dispensed for those particular subjects. 
(c) Subjects will return to the study site 7 days following the Week 7/Early Termination visit. 
(d) If subjects return for the Follow-Up (Week 7) visit after the allowed study window (≥ Day 57). 
(e) If subjects return after the Follow-Up (Week 7) visit for a repeat assessment, that visit and any 
additional visits will be identified as a Repeat Follow-Up visit. 
(f) This considers the last post-baseline values collected/derived for a particular set of data after study 
drug of NYX-2925 was dispensed (including unscheduled and repeated measurements/assessments). 
(g) This is used for considering any worst-case, lowest, highest, etc. values for any post-baseline data 
after study drug of NYX-2925 was dispensed.  Examples of this are used for clinical laboratory tests 
and C-SSRS data. 
(h) This is used for combining all post-baseline data after study drug of NYX-2925 was dispensed.  
Examples of this are used for study drug accountability, compliance, and treatment exposure. 
 
 
 
Protocol/CRF 
Term 
Analysis Visit 
Study Day Window 
Screening 
Screening(a) 
≤ Day -8 
Baseline 
Baseline 
Day -7 to Day -1 
Week 1 
Week 1 
Day 1 to Week 1 Visit - 1 
Week 2 
Week 2 
Week 1 Visit Day to Week 2 Visit - 1 
Week 3 
Week 3 
Week 2 Visit Day to Week 3 Visit - 1 
Week 4 
Week 4 
Week 3 Visit Day to Week 4 Visit - 1 
Week 5 
Week 5 
Week 4 Visit Day to Week 5 Visit - 1 
Week 6 
Week 6 
Week 5 Visit Day to Week 6 Visit - 1 
Follow-Up/Week 7 
Follow-Up (Week 7) 
Week 6 Visit Day to Follow-Up Visit 
N/A 
After Follow-Up (Week 7)(a) 
After the Follow-Up Visit 
(a) Screening and after Follow-Up (Week 7) values will be displayed in listings, but not included 
summary tables. 
5.6 Data Imputations 
Standard methods described below will be used for imputing missing data and character values in 
numeric collected parameter data. 


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5.6.1 Character Values in Numeric Data 
Characters such as “<, >, and/or =” may be included in some parameter data values that are supposed 
to be collected in a numeric format.  This is most commonly seen in laboratory data.  Analysis values 
for results with “<=” or “>=” will be analyzed with those characters stripped from the collected result 
(i.e. “<=1.030” = “1030” and “>=100” = “100”). 
Analysis values with only “<” will be handled using these methods: 
• 
For precision data collected with at least one number after the decimal point, the analysis 
value will be the numeric value minus 1 extra precision unit (i.e. “<0.1” = “0.09”). 
• 
For whole numbers collected and the value reported as “<0” then the analysis value will be 0. 
• 
For other whole numbers collected, the analysis value will be the numeric value minus 1. 
Analysis values with only “>” will be handled using these methods: 
• 
For precision data collected with at least one number after the decimal point, the analysis 
value will be the numeric value plus 1 extra precision unit (i.e. “>5.25” = “5.251”). 
• 
For whole numbers collected, the analysis value will be the numeric value plus 1. 
For listing purposes, the collected results will be displayed in the CSR listings and appendices (i.e. 
“<5.0” over “4.99”). 
5.6.2 Missing Analysis Values 
No missing analysis values will not be imputed for this study. 
5.6.3 Missing or Partial Dates 
Adverse Event Start Dates: 
• 
Method 1 – Earliest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the earliest possible date that is ≥ to the screening date. 
• 
Method 2 – Latest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the latest possible date that is ≤ to the latest possible adverse event end date.  
If the adverse event is ongoing after the final visit for the subject, then the final visit 
date will be used. 
Prior/Concomitant Medications Start Dates: 
• 
Method 1 – Earliest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the earliest possible date that is ≥ to the subject’s date of birth. 
• 
Method 2 – Latest Possible Start Date: 
o If any combination of the year, month, and/or day are missing then the start date will 
be set to the latest possible date that is ≤ to the latest possible medication end date.  If 
the medication is ongoing after the final visit for the subject, then the final visit date 
will be used. 
 


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Adverse Event and Prior/Concomitant Medications End Dates: 
• 
Method 1 – Earliest Possible End Date: 
o If any combination of the year, month, and/or day are missing then the end date will 
be set to the earliest possible date that is ≥ to the earliest possible adverse 
event/medication start date. 
• 
Method 2 – Latest Possible End Date: 
o If any combination of the year, month, and/or day are missing then the end date will 
be set to the latest possible date that is ≤ to the subject’s final visit date.  If the 
adverse event/medication is ongoing after the final visit for the subject, then the final 
visit date will be used. 
Medical History Disease Onset Dates: 
• 
If year is missing, then the date will not be imputed. 
• 
If both the month and day are missing, then the date will be imputed as July 1st with the year 
collected.  However, if this imputed date is ≥ to the screening date then the imputed date will 
be the screening date minus 1 day. 
• 
If only the day is missing, then the date will be imputed as the 15th with the year and month 
collected.  However, if this imputed date is ≥ to the screening date then the imputed date will 
be the screening date minus 1 day. 
5.7 Multiplicity Adjustments 
No multiplicity adjustments will be made for this study. 
5.8 By-Center Analyses 
No formal by-center analyses is planned for this study. 
5.9 Subpopulation Analyses 
No formal subpopulation analyses are planned for this study. 
6. Analysis Populations 
Subjects who screened for the study, but were excluded from any of the analysis populations below 
will have the reasons why presented in a subject listing and frequency distribution tables. 
6.1 Safety Population 
All subjects who were dispensed study drug during the Day 1 (Baseline) visit and did not return all 
the study drug in their next visit will be in the safety population.  It will be assumed that these 
subjects in the safety population have taken at least one dose of study drug.  Subjects in the safety 
population will be used for all analyses of safety data and will be analyzed based on the actual 
treatment received within each treatment period in the study. 
6.2 Efficacy Population 
The efficacy population will be based on subjects included in the safety population and have at least 
one post-baseline visit after receiving NYX-2925 20 mg PO QD.  Subjects in the efficacy population 
will be analyzed based on the planned treatment they were supposed to receive within each treatment 
period.  The efficacy population will be the primary analysis population used for this study. 


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6.3 PP Population 
The Per Protocol (PP) population will be based on all subjects in the efficacy population and the 
following criteria: 
• 
Subjects first received Placebo for 2 weeks, then NYX-2925 20 mg PO QD for 2 weeks, and 
then NYX-2925 200 mg PO QD for 2 weeks; 
• 
Subjects received the appropriate study drug for each treatment period; 
• 
Subjects did not use any of the prohibited concomitant medications listed in Section 8.8 of 
the protocol; 
• 
Subjects who have an overall NYX-2925 study drug treatment compliance between 80% and 
125%; 
Subjects in the PP population will be defined based on a review of the relevant data by the Sponsor 
prior to database lock and subjects may be excluded due to particular major protocol deviations.  
Subjects in the PP population will be analyzed based on the planned treatment they were supposed to 
receive within each treatment period. 
7. Disposition, Baseline, and Other Characteristics 
All subjects will be summarized in the tables based each study treatment they were dispensed and 
received.  The maximum strength study drug dose received, “Screen Failure” or “Not Treated” will be 
displayed in the subject listings. 
7.1 Subject Disposition 
All subjects who were screened in the study will be summarized in a frequency distribution table by 
their following status after the baseline visit where the denominator will be the number of subjects 
screened: 
• 
Screened and Treated 
• 
Screened and Not Treated 
Any subjects “Screened and Not Treated” will be subcategorized for the following reasons collected 
on the CRF:  does not meet inclusion/exclusion criteria, withdrew consent, adverse event, protocol 
non-compliance, lost to follow-up, pregnancy, sponsor terminated the study, and other.  “Other” will 
be displayed on the tables if collected on the CRF and no other standardized term may be used. 
Frequency distributions of the subjects who completed each treatment period and the overall study 
will be summarized.  Furthermore, frequency distributions for the subjects who discontinued 
prematurely will be summarized along with the primary reason for withdrawal or discontinuation 
collected on the CRF. 
The subject disposition listings will include all subjects with the following data:  date informed 
consent signed, IRB approval date, date of completing or discontinuing from the study, date of last 
dose of study drug (if applicable), study completion status, and primary reason for study 
discontinuation (if applicable), and the date of the follow-up visit or reason why it was not done.  
Subjects who received study drug will have their calculated study days presented next to the dates in 
parentheses. 


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7.2 Demographics and Disease History 
Demographics and baseline characteristics will be summarized for the safety, efficacy, and PP 
populations.  Descriptive statistics will be calculated for the following continuous demographic and 
baseline characteristic variables at screening:  age, height, weight, and body mass index (BMI).  
Frequency distributions will be tabulated for the following categorical demographic variables:  sex, 
childbearing potential, race, and ethnicity.  Sex will be listed and summarized in the tables even 
though all the subjects screened for this study are females. 
The onset disease history for fibromyalgia will be summarized based on the number of years in the 
demographics and baseline characteristics table.  The fibromyalgia event will also be provided in the 
medical history subject listing, but not in the summarized in the medical history table. 
The number of years for fibromyalgia be calculated as the (number of days from the onset date to the 
latest signed informed consent date) / 365.25 rounded off by one number after the decimal point.  For 
partial dates collected, the imputation fibromyalgia onset date described in Section 5.6.3 will be used. 
Subject listings will include the subject’s date of birth, any reasons why the subject does not have 
childbearing potential (if applicable), and all continuous/categorical variables listed above. 
7.3 Subject Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria will be provided in a subject listing where each subject number not 
meeting each criterion will be displayed.  The inclusion/exclusion criteria numbers not met will be 
listed with a brief description of the inclusion/exclusion criteria. 
7.4 Medical History 
Medical history data will be mapped using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 19.0 to system organ class (SOC), and preferred term (PT).  This data will be 
summarized in a frequency distribution.  Subjects may have more than one medical history record per 
SOC and PT.  At each level of subject summarization, a subject will be counted once if he/she reports 
one or more medical history record at that specific level.  Subjects must have a medical history of 
fibromyalgia in order to be eligible for the study.  Therefore, fibromyalgia will not be counted in the 
medical history frequency distribution table, but a footnote will be added that all subjects had 
fibromyalgia in the safety population.  A frequency distribution table will be displayed by each study 
drug treatment period received and all subjects even though the medical history information was 
collected prior to dispensing study drug. 
Additionally, collected data on the CRF will be listed by subject, verbatim body system, verbatim 
medical condition/procedure, onset date, and ongoing status/end date. 
8. Study Drug Exposure and Other Medications 
8.1 Study Drug Accountability 
Subjects will be dispensed study drug based on fixed treatment periods at visits Day 1 (Baseline), 
Week 2, and Week 4.  In the event the subject comes in for an unscheduled visit prior to a weekly 
visit, they may be dispensed additional study drug.  Additional study drug may be dispensed at any 
study visit or unscheduled visit if the subject will need study drug beyond the two week allotment 


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provided at Day 1, Week 2 and Week 4. Capsule strengths for NYX-2925 are 10 mg and 100 mg.  
Subjects will be instructed to take 2 capsules of investigational product once daily by mouth. 
The following data will be collected and derived at each start and end to the study drug accountability 
treatment periods/visit intervals: 
Parameter 
Origin/Derivation 
Capsules Dispensed Amount 
CRF 
Capsules Returned Amount 
CRF 
Expected Number of 
Capsules Taken 
Derived:  Date Returned – Date Dispensed + 1 (where the 
maximum would be 30 because 30 capsules are issued at each 
dispensing visit) 
Estimated Number of 
Capsules Taken 
Derived:  Number of Capsules Dispensed Amount – Number of 
Capsules Returned Amount 
Treatment Compliance (%) 
Derived:  100 x Estimated Number of Capsules Taken / Expected 
Number of Capsules Taken (rounded off by one number after the 
decimal point) 
The Overall NYX-2925 Treatment Compliance (%) will be calculated as: 
• 
100 x ∑ (Estimated Number of Capsules Taken at All Study Drug Return Visits After NYX-
2925 20 mg or 200 mg PO QD was Dispensed) / ∑ (Expected Number of Capsules Taken at 
All Study Drug Return Visits After NYX-2925 20 mg or 200 mg PO QD was Dispensed) 
and rounded off by one number after the decimal point 
A subject will be classified as being compliant with study drug administration if their calculated 
compliance by each treatment period and overall is between 80% and 125%, inclusive.  Descriptive 
statistics will be summarized for treatment compliance by returning analysis visits Week 2 (Placebo), 
Week 4 (NYX-2925 20 mg PO QD), Week 6 (NYX-2925 200 mg PO QD), and Overall (NYX-2925 
20 mg and 200 mg PO QD).  The following categorical ranges will be summarized in a table for those 
same analysis visits and overall: 
• 
<80%, 80-125%, >125%, and Not Reported 
Any study drug not returned during a subject’s visit where study drug compliance is assessed will 
assume that all of that study drug was taken by the subject for analysis purposes.  No adjustments will 
be made even if comments are documented on the CRF that stated lost samples were reported by the 
subjects.  All study drug accountability comments will be provided in a subject listing.  If a subject is 
lost to follow-up after being dispensed study drug, then the study drug returned and overall treatment 
compliance will be set to missing.  Any unscheduled visits will be summarized within the study 
treatment periods based on the study drug dispensed (Placebo, NYX-2925 20 mg PO QD, or NYX-
2925 200 mg PO QD). 
 
 


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8.2 Study Drug Exposure 
The study will include the following fixed placebo period and active treatment periods with 2 dose 
strengths: 
• 
Placebo PO QD for 2 weeks 
• 
NYX-2925 20 mg PO QD for 2 weeks 
• 
NYX-2925 200 mg PO QD for 2 weeks 
Each bottle number assigned to a subject will be verified that correct study drug was given based on 
the each treatment period.  Any incorrect study drug bottle given where the estimated number of 
capsules taken defined in Section 8.1 is greater than zero, will be defined as a major protocol 
deviation.  Study drug exposure will be listed and summarized based on the treatment periods the 
subjects received. 
The number of study days of study drug exposure will be summarized using descriptive statistics 
based on the date of the last dose of study drug collected on the CRF for each treatment period.  If the 
date/time of the last dose of study drug was not fully collected for a treatment period, then the date of 
returning the study drug will be used instead.  If a subject is lost to follow-up after being dispensed 
study drug and the date of the last dose of study drug was not collected, then the number of study 
days will be set to missing for that specific treatment period. 
8.3 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD), version 03-2016 and will be classified according to the default Anatomical 
Therapeutic Chemical (ATC) classification system code (up to 4 levels), WHO-DD Drug Name, and 
Preferred Term (PT). 
Due to the nature of this study, the date and time of first dose of study drug was not collected on the 
CRF.  Therefore, the following algorithm will be used to determine prior medications: 
• 
Earliest Possible Medication Start Date ≤ Day 1 (Baseline) Visit Date 
The following algorithm will be used to determine concomitant medications: 
• 
Latest Possible Medication Stop Date ≥ Day 1 (Baseline)Visit Date 
Depending on the start and stop dates of the medication, it is possible for a medication to be classified 
as both prior and concomitant. 
Prior and concomitant medications will be summarized by the ATC Class Level 3 category (or Level 
2 if there is not an applicable Level 3 category) and PT.  Subjects may have more than one 
medication per ATC category and PT.  At each level of subject summarization, a subject will be 
counted once if he/she reports one or more medications at that specific level. 
The prior medication frequency distribution table will be displayed by each study drug treatment 
period received and all subjects even though the prior medication information was collected prior to 
dispensing study drug.  The concomitant medication frequency distribution table will be displayed by 
the study drug treatment period based on the earliest possible start date described in Section 5.6.3 and 
prior medications that are not stopped on the Day 1 (Baseline) visit. 


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9. Pharmacodynamic Analyses 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.3 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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12. Safety Analyses 
12.1 Adverse Events 
Treatment-emergent adverse events (TEAEs) will be those occurring during or after administration of 
the first dose of study drug until 30 days after the final dose of study drug.  The date and time of first 
dose of study drug was not collected on the CRF for all subjects.  Therefore, the following algorithm 
will be used to determine if the adverse events are treatment-emergent without a date and time of first 
dose of study drug: 
• 
Earliest Possible AE Start Date ≥ Day 1 (Baseline) Visit and Study Drug Dispensation and 
• 
Latest Possible AE Start Date ≤ 30 Days After the Final Dose of Study Drug 
AEs that started prior to first dosing of study drug, but become worse in severity after receiving study 
drug will be considered treatment-emergent.  The determination of whether or not an adverse event is 
classified as “treatment emergent” (i.e. TEAE) is not determined by the classification of “relationship 


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to study drug” collected on the CRF, but rather by the temporal relationship of the adverse event to 
the administration of study drug. 
A related study drug TEAE is defined as any TEAE with at least a possible relationship to the study 
drug as assessed by the investigator or that is missing the assessment of causal relationship whose 
relationship to the study drug could not be ruled out.  Relationships of “possibly related”, “probably 
related”, or missing are collected on the CRF, then those adverse events will be considered related 
study drug TEAEs.  If the “unrelated” or “unlikely related” are collected on the CRF, then those 
adverse events will be considered not related study drug TEAEs. 
Severity is assigned to each adverse event collected on the CRF.  Maximum severity has the 
following order: “life threatening”, “severe”, “moderate”, and “mild” as possible collection options 
on the CRF.  A missing severity will be treated as “unknown” for analysis purposes. 
All adverse events will be coded and summarized by System Organ Class (SOC) and Preferred Term 
(PT) based on Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 coding 
dictionary.  This data will be summarized in a frequency distribution.  Subjects may have more than 
one TEAE record per SOC and PT.  At each level of subject summarization, a subject will be counted 
once if he/she reports one or more TEAE record at that specific level.  For tables summarized by SOC 
and PT, the events will be displayed in the order of descending frequency counts for all treatments by 
SOC and then PT within SOC. 
The number of subjects with at least one of the following adverse events, percentages for each 
category by treatment, and the number of total events will be included in an overall treatment-
emergent adverse events summary table: 
• 
Any TEAEs 
• 
Related TEAEs 
• 
Maximum Severity TEAEs 
• 
Serious TEAEs 
• 
Related, Serious TEAEs 
• 
TEAEs Leading to Study Discontinuation 
• 
Related TEAEs Leading to Study Discontinuation 
• 
TEAEs Leading to Death 
Summaries including the number of subjects and percentages of the following adverse events by SOC 
and PT will be provided: 
• 
Any TEAEs 
• 
Related TEAEs 
• 
Maximum Severity TEAEs 
• 
Serious TEAEs 
• 
TEAEs Leading to Study Discontinuation 
Additionally, TEAEs will be summarized by descending frequency counts of PT for all treatments.  
All adverse event data collected will be provided in subject listings.  Subset subject listings will also 
be provided by serious treatment-emergent adverse events and deaths; by treatment-emergent adverse 
events leading to study discontinuation; any adverse events that are not considered to be treatment-
emergent; by serious adverse events and deaths that are not considered to be treatment-emergent; and 
by adverse events leading to study discontinuation that are not considered to be treatment-emergent. 


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12.2 Clinical Laboratory Tests 
Clinical laboratory tests for hematology, serum chemistry, and urinalysis will be summarized: 
 


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13. Other Analyses 
13.1 Protocol Deviations 
Protocol deviations are collected during the study in a log maintained by the investigative site.  Prior 
to database lock, the protocol deviations will be entered into an Excel spreadsheet and reviewed for 
the following reasons: 
• 
Standard study terminology deviation categories assigned 
• 
Severity (major versus minor) assigned 
• 
If a subject should be excluded from the PP population 
After database lock it may be determined that additional protocol deviations occurred.  As a result, 
any additional protocol deviations found after database lock will be included with previous protocol 
deviations.  Potential protocol deviations discovered after database lock may result excluding subjects 
from the PP population. 
A subject listing will include the treatment period, deviation category, protocol deviation, occurrence 
date with the corresponding study day, severity (major versus minor), and if the protocol deviation 


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resulted in excluding a subject from the PP population.  A frequency distribution table will be created 
to summarize only major protocol deviations by the assigned deviation categories. 
14. Interim Analyses 
An interim analysis will be performed based on a pre-database lock data cut after the 11th subject has 
completed the trial.  Selected analyses will be completed.  Given that this exploratory pilot study is 
single-blind and Phase 2, there will be no adjustments to Type I error. 
15. Planned CSR Tables, Figures, and Listings in Section 14 
The following are planned summary tables, figures, and listings (TFLs).  TFLs will be numbered 
according to the nomenclature used to support the CSR in Section 14.  The final TFL numbering may 
be different from the SAP.  No amendment will be made for changes in TFL numbering.  All titles, 
footnotes, and headers specified in the mock TFL shells will be displayed in the produced output 
unless otherwise specified.  Notes to programmers will not be included in the TFLs.  There will be a 
footnote in all TFLs that includes the SAS® version number, company creating the output, program 
name, the date/time that the output was produced, and the dataset(s) referenced for the output.  
Additional footnotes may be added to help explain/support particular data values that are not 
displayed in the mock TFL shells.  A separate mock TFL shells document will be created to support 
the appearances of these planned TFLs. 
Number 
Population* 
TFL: Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number 
Population* 
TFL: Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number 
Population* 
TFL: Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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Number 
Population* 
TFL: Title 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
   
 
 
   


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Number 
Population* 
TFL: Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number 
Population* 
TFL: Title 
14.3 Safety and Other Data Summary Tables and Listings 
14.3.1 Adverse Event Tables 
14.3.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number 
Population* 
TFL: Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number 
Appendix Title 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number 
Appendix Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
, 


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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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[23] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix I: Schedule of Assessments 


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