Clinical trial NCT02806908
Conditions: Narcolepsy Excessive Sleepiness
Keywords: Driving
Sponsor: Jazz Pharmaceuticals
Start date: 2016-06-01; Completion date: 2019-05-19
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This trial is a randomized, double-blind, placebo-controlled, crossover study to evaluate the effect of JZP-110 on driving performance in subjects with excessive sleepiness due to narcolepsy.

Detailed description:

Arms: arm 1: Once daily dosing arm 2: 150 mg/day for first 3 days and 300 mg/day for next 4 days
Interventions: intervention 1: JZP-110 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 

































































































































































































SAP_000.pdf: 
Jazz Pharmaceuticals 
 
 
Statistical Analysis Plan – JZP-110 Protocol 15-005 
AUG 9, 2019 
 
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STATISTICAL ANALYSIS PLAN 
 
FINAL VERSION: 2.0 
DATE OF PLAN: 
9-AUG-2019 
 
BASED ON: 
15-005 Protocol Amendment 5, Feb 7, 2018 
 
STUDY DRUG: 
JZP-110, a.k.a. solriamfetol 
PROTOCOL NUMBER: 
15-005
STUDY TITLE: 
A Randomized, Double-Blind, Placebo-Controlled, Crossover On- 
Road Driving Study Assessing the Effect of JZP-110 on Driving 
Performance in Subjects with Excessive Sleepiness Due to Narcolepsy
 
SPONSOR: 
Jazz Pharmaceuticals 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 




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Statistical Analysis Plan – JZP-110 Protocol 15-005 
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History of Change: 
Version 2.0 from 1.0: 
1. Update the visit window in section 5.4.4 to map all the unscheduled visits 
2. Remove Predose from the analysis model for PVT 
3. Add Treatment sequence to section 7.5.1. 
4. Update medical history in section 6.5 to change the reporting approach 
5. Add the range of THAT total score 
6. Clarify mITT population includes subjects with SDLP 2 hr post-dose at any post-baseline 
visit 
7. Clarify the per-protocol population and the procedure to identify PP population. 
8. Visit window is updated to clarity the scheduled visit. 
 
 
 


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Statistical Analysis Plan – JZP-110 Protocol 15-005 
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TABLE OF CONTENTS 
1.
LIST OF ABBREVIATIONS .......................................................................................8
2.
INTRODUCTION ......................................................................................................10
3.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11
3.1.
Study Objectives .........................................................................................................11
3.1.1.
Primary Objective .......................................................................................................11
3.1.2.
Secondary Objective ...................................................................................................11
3.2.
Study Endpoints ..........................................................................................................11
3.2.1.
Primary Efficacy Endpoints ........................................................................................11
3.2.2.
Secondary Efficacy Endpoints ....................................................................................11
3.2.3.
Safety Endpoint ..........................................................................................................11
4.
STUDY DESIGN .......................................................................................................13
4.1.
Summary of Study Design ..........................................................................................13
4.2.
Sample Size Considerations .......................................................................................14
4.2.1.
Sample Size Justification ............................................................................................14
4.3.
Randomization ............................................................................................................14
4.4.
Clinical Assessments ..................................................................................................14
4.4.1.
Efficacy Assessment ...................................................................................................14
4.4.2.
Safety Assessment ......................................................................................................15
5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................16
5.1.
General Summary Table and Individual Subject Data Listing Considerations ..........16
5.2.
Analysis Populations ..................................................................................................16
5.2.1.
Modified Intent-to-treat Analysis Population .............................................................16
5.2.2.
Per-Protocol Analysis Population ...............................................................................16
5.2.3.
Safety Analysis Population .........................................................................................17
5.3.
Baseline Definition .....................................................................................................17
5.4.
Derived and Transformed Data ..................................................................................17
5.4.1.
Age at Baseline ...........................................................................................................17
5.4.2.
Study Day ...................................................................................................................17
5.4.3.
Change from Baseline .................................................................................................17
5.4.4.
Visit Windows ............................................................................................................17
5.4.5.
Multiple Assessments .................................................................................................18


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Statistical Analysis Plan – JZP-110 Protocol 15-005 
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5.5.
Handling of Missing Data ...........................................................................................18
6.
STUDY POPULATION .............................................................................................19
6.1.
Subjects Disposition ...................................................................................................19
6.2.
Screen Failures ............................................................................................................19
6.3.
Protocol Deviations ....................................................................................................19
6.4.
Demographic and Baseline Characteristics ................................................................19
6.5.
Medical History ..........................................................................................................19
7.
EFFICACY .................................................................................................................20
7.1.
General Considerations ...............................................................................................20
7.2.
Statement of the Null and Alternate Hypotheses ........................................................20
7.3.
Subgroup Analyses .....................................................................................................20
7.4.
Multiple Comparisons and Multiplicity ......................................................................20
7.5.
Analysis of the Primary Efficacy Endpoint ................................................................20
7.5.1.
Primary Efficacy Analysis ..........................................................................................20
7.5.2.
Sensitivity Analyses of the Primary Efficacy Results ................................................21
7.6.
Analysis of the Secondary Efficacy Endpoints ..........................................................21
7.6.1.
Secondary Efficacy Analysis of Continuous Endpoints .............................................21
7.6.2.
Secondary Efficacy Analysis of Dichotomous Endpoints ..........................................22
7.7.
Analysis of the Other Efficacy Endpoints ..................................................................23
8.
SAFTY AND TOLERABILITY ................................................................................24
8.1.
Overall Summary of Tolerability ................................................................................24
8.2.
Adverse Events ...........................................................................................................24
8.2.1.
Summaries of Adverse Event Incidence Rates for All Subjects .................................24
8.3.
Total Duration of Therapy and Compliance ...............................................................25
8.4.
Prior Medications ........................................................................................................25
8.5.
Concomitant Medications ...........................................................................................25
8.6.
Routine Laboratory Data ............................................................................................25
8.7.
Vital Signs ..................................................................................................................25
8.8.
ECG ............................................................................................................................26
8.9.
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................26
8.9.1.
C-SSRS Outcomes/Composite Scores ........................................................................26
8.9.2.
C-SSRS Analyses .......................................................................................................27
9.
REFERENCE LIST ....................................................................................................28


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10.
APPENDIX .................................................................................................................29
10.1.
10.1 Additional reference tables .................................................................................29
10.2.
Date Imputation Rules ................................................................................................32
 
 


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LIST OF TABLES 
Table 1
List of Abbreviations ....................................................................................................8
Table 2
Treatment Sequence Schedule ....................................................................................14
Table 2
Visit Window ..............................................................................................................18
Table 3
Vital Sign Reference Range ........................................................................................26
Table 4
Schedule of Events .....................................................................................................29
Table 5
Critical Values of Max McNemar Test for Sample Size K = 8 to 99, 
Significance level α = 0.1, 0.05, 0.025 and 0.01. .......................................................31
LIST OF FIGURES 
Figure 1
Overview of 15-004 Study Design .............................................................................13
 
 


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1.
LIST OF ABBREVIATIONS 
Table 1 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of variance 
BMI 
Body mass index 
CI 
Confidence interval 
C-CASA 
Classification Algorithm of Suicide Assessment 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
MCC 
Microcrystalline Cellulose 
HR 
Heart rate 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
PAP 
Positive Airway Pressure 
PP 
Per Protocol 
PR 
Pulse Rate 
PT 
Preferred term 
PVT 
Psychomotor Vigilance Test 
RT 
Reaction Time 
SAE 
Serious Adverse Event 
SAFTE 
Sleep, Activity, Fatigue, and Task Effectiveness 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDLP 
Standard deviation of lateral position 
SDS 
Standard deviation of speed 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
THAT 
Toronto Hospital Alertness Test 
TFLs 
Tables, figures, and listings 


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WASO 
Wake Time After Sleep Onset 
WHO 
World Health Organization 
 


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2.
INTRODUCTION 
 
This statistical analysis plan (SAP) describes the planned analyses and data displays to be 
included in the Clinical Study Report (CSR) for Protocol No. 15-005 
The SAP is based on:  
x
Protocol No. 15-005, Amendment 5, February 7, 2018 
x
ICH guidelines E4 and E9 (Statistical Principles for Clinical Trials)  
The purpose of this document is to provide details on study populations, how the variables will 
be derived, how missing data will be handled and to provide details on statistical methods to be 
used to analyze the safety and efficacy data for Study 15-005. Any additional analyses or 
deviation from the analyses outlined in this plan will be documented with rationale in the final 
CSR. 


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3.
STUDY OBJECTIVES AND ENDPOINTS 
3.1.
Study Objectives 
3.1.1.
Primary Objective 
The primary objective of this study is to evaluate the effect of JZP-110 (solriamfetol) on driving 
performance. 
3.1.2.
Secondary Objective 
The secondary objectives of the study are:  

to evaluate the safety and tolerability of JZP-110 

to explore SAFTE (Sleep, Activity, Fatigue, and Task Effectiveness) modeling 
using driving, Psychomotor Vigilance Test (PVT) and sleep data 
3.2.
Study Endpoints 
3.2.1.
Primary Efficacy Endpoints 

Standard deviation of lateral position (SDLP) at 2 hours post-dose 
3.2.2.
Secondary Efficacy Endpoints 

SDLP at 6 hours post-dose 

Proportion of subjects with improved or impaired driving on JZP-110 compared 
to placebo 

Standard deviation of Speed (SDS) 

Driving lapses 

PVT measures 
Inverse reaction time (1/RT) 
Lapses (RT>500 ms) 
Mean reaction time (RT) 
Errors of commission 

Toronto Hospital Alertness Test (THAT) 

Sleep, Activity, Fatigue and Task Effectiveness (SAFTE) modeling using driving, 
PVT and sleep data will be generated 
3.2.3.
Safety Endpoint 

Adverse events (AEs) (Section 8.2) 

Vital signs (Section 8.7) 


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
Physical examination 

Columbia Suicide Severity Rating Scale (C-SSRS) assessments 
 


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4.
STUDY DESIGN 
4.1.
Summary of Study Design 
This trial is a 2-week, randomized, double-blind, placebo-controlled crossover study of the effect 
of JZP-110 on driving performance, safety and tolerability in adult subjects with narcolepsy 
(Figure 1). Subjects will be recruited at sleep clinics or Clinical Sites. Eligibility will be 
determined through screening procedures, including careful confirmation of narcolepsy diagnosis  
at Clinical Sites and a practice driving test at the Driving Test Site. 
Eligible subjects will be randomized to receive either JZP-110 (150 mg/day for 3 days, followed 
by 300 mg/day for 4 days) or the matching placebo for 7 days, and will then crossover to receive 
the other treatment for 7 days (Figure 1, Table 2). On Day 7 of each treatment period, all 
randomized subjects will have a study visit to undergo two driving performance tests, one at 2 
hours (between 1 to 3 hours) and the other at 6 hours (between 5 to 7 hours) after the morning 
dose. The Psychomotor Vigilance Test (PVT) will be administered at pre-dose and prior to each 
driving test. Actigraphy and a sleep diary will be used to assess daily sleep patterns. The Toronto 
Hospital Alertness Test (THAT) will be administered at the end of each treatment period. A 
follow-up visit will be performed approximately 7 days after the final dose of study drug. The 
initial screening visit, and the follow-up visit will be conducted at the Clinical Sites and the 
remaining Baseline visit and two driving test visits, will be conducted at the Driving Test Site. 
For Schedule of Events, see Table 5 in the Appendix. 
Figure 1 
Overview of 15-005 Study Design 
 


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Table 2 
Treatment Sequence Schedule 
 
Treatment Period 1   
Treatment Period 2 
Treatment Sequence 1 
Placebo 
JZP-110 
Treatment Sequence 2 
JZP-110 
Placebo 
4.2.
Sample Size Considerations 
4.2.1.
Sample Size Justification 
A sample size of 36 subjects will provide 90% power to detect a mean difference of 2.0 cm on 
the primary outcome measure of SDLP (Ramaekers et al. 2006 and Verster et al. 2008). This 
calculation assumes a standard deviation of 3.0 cm and a two-sided significance level of 0.05 
using a paired t-test. To account for 10% dropouts without evaluable SDLP data, a sample size of 
33 subjects is planned. 
4.3.
Randomization 
All eligible subjects will be randomly assigned to treatments via an interactive Response 
Technology (IRT) system. Subjects will be randomized in a 1:1 ratio to receive JZP-110 (150 
mg/day for 3 days, followed by 300 mg/day for 4 days) or the matching placebo for 7 days, and 
will then crossover to receive the other treatment for 7 days.  
4.4.
Clinical Assessments 
4.4.1.
Efficacy Assessment 
Driving performance will be assessed using a standardized on-road driving test on Day 7 (Visit 
3) and on Day 14 (Visit 4). The following variables to determine driving performance will 
include: SDLP, standard deviation of speed (SDS) and number of driving lapses. 
The THAT is a 10-item self-report questionnaire designed to measure perceived alertness in the 
preceding week. The THAT will be administered at the end of each treatment period. The total 
score of THAT can range between 0 to 50 and higher score indicates greater alertness. 
The PVT is a sustained-attention, reaction-timed task that measures the speed with which 
subjects respond to a visual stimulus. The PVT will be administered over 10 minutes with visual 
stimuli appearing randomly at variable intervals of 2-10 seconds. The PVT will be administered 
at screening visit for practice only and at pre-dose and prior to each driving test on Day 7 (Visit 
3) and Day 14 (Visits 4). The PVT measures will include: lapses (RT>500 ms), mean reaction 
time (RT), inverse reaction time (1/RT), and errors of commission. 
Actigraphy and a sleep diary will be used to assess daily sleep patterns. 


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4.4.2.
Safety Assessment 
Safety will be assessed throughout the study. Screening procedures will include physical 
examination, electrocardiogram (ECG), and clinical laboratory tests. During the study, clinically 
significant adverse changes in ECGs, routine laboratory tests, and physical examinations are 
considered AEs. Any subject complaint associated with such an abnormal finding will also be 
reported as an AE. The C-SSRS will be completed at screening and each visit. The Investigators 
from the Clinical Sites and the Driving Test Site will share information about all safety aspects 
of the study and Jazz Pharmaceuticals will facilitate development of a communication plan for 
managing, recording, and reporting adverse events. 
 


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5.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
5.1.
General Summary Table and Individual Subject Data Listing 
Considerations 
Unless otherwise specified, for numeric data, descriptive statistics will include the number of 
subjects with data to be summarized (n), mean, standard deviation (SD), median, minimum (min) 
and maximum (max). The same number of decimal places as in the raw data will be presented 
when reporting min and max, 1 more decimal place than in the raw data will be presented when 
reporting mean and median, and 2 more decimal places than in the raw data will be presented 
when reporting SD. If the raw data have 3 decimals or more, 3 decimals will be presented for 
mean, median, min and max, and SD. 
All categorical/qualitative data will be presented using absolute and relative frequency counts 
and percentage. All percentages will be presented with one-decimal point. Percentages equal to 
100 will be presented as 100% and percentages will not be presented for zero frequencies but the 
categories whose counts are zero will be displayed. 
P-value > 0.9999 will be presented as ‘>0.9999’ and p-value < 0.0001 will be presented as ‘< 
0.0001’. 
All analyses and summary outputs will be generated by using SAS® version 9.4. 
All data collected in this study will be presented in by-subject listings. 
5.2.
Analysis Populations  
5.2.1.
Modified Intent-to-treat Analysis Population 
The modified intent-to-treat (mITT) analysis population will comprise all randomized subjects 
who receive at least one dose of study medication and have evaluable SDLP data at 2 hours post-
dose in any post-baseline visit. 
This population will be used for the primary, secondary, and other efficacy endpoints. If a 
subject in the mITT population does not have an assessment for a particular endpoint, that 
subject will be excluded from the analysis of that endpoint. 
5.2.2.
Per-Protocol Analysis Population 
The per-protocol analysis population will be the sub set of subjects from the mITT population 
who complete the trial according to protocol specification without a major deviation that 
potentially have an impact on the efficacy endpoints. The final list of protocol deviations 
resulting in exclusion of a subject from the PP will be determined and approved prior to Data 
base Lock. This population will be used to perform secondary analyses for the primary and 
secondary efficacy endpoints. 


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5.2.3.
Safety Analysis Population  
The safety analysis population will consist of all subjects who received at least one dose of study 
medication. This population will be analyzed for all safety endpoints. 
5.3.
Baseline Definition 
In general, the Baseline measurement for a variable is defined as the last non-missing value from 
the baseline visit measured prior to the first dose of the study drug. If a subject has repeated 
measurements from the baseline visit, then the last repeated non-missing value will be used. If 
there is not a value from the scheduled baseline visit, the last non-missing value from other 
screening or unscheduled visits measured prior to the first dose of study drug will be used. For 
Actigraphy, the Baseline value is derived as an average of data from 7 days prior to the first dose 
of the study drug. 
5.4.
Derived and Transformed Data 
5.4.1.
Age at Baseline  
The age at baseline is the age at Inform Consent date. 
5.4.2.
Study Day 
A study day will be assigned as follows: 
x
The first dose of study drug is designated as Day 1.  
x
For visit days after Day 1, study day = visit date - Day 1 date + 1.  
x
For visit days prior to Day 1, study day = visit date - Day 1 date. Thus, study days for 
screening visit are negative numbers. There is no “Day 0”.  
x
The end date of treatment for each subject is the subject’s last dose date in the study.  
x
The end date of the study for each subject is defined as the date of the subject’s last 
assessment including the safety follow-up in the study.  
5.4.3.
Change from Baseline 
Change from Baseline is the collection/assessment value subtracted from the collected or derived 
Baseline value. 
5.4.4.
Visit Windows 
All visits, including scheduled visits, unscheduled visits, and early termination (ET) visits will be 
eligible for being flagged as the “analyzed record” within the analysis visit window (Table 3). A 
subject’s individual analysis visit window could potentially contain more than one visit.  In the 
event of multiple visits falling within an analysis visit window or in case of a tie, the following 
rules will be used in sequence to determine the “analyzed record” for the analysis visit window: 
x
If there is a scheduled visit/week for the analysis visit window, then the scheduled 
visit/period data will be used. 


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x
If there is no scheduled visit/period for the analysis visit window, the unscheduled visit 
closest to the scheduled visit day will only be used for that scheduled visit/period. 
The data not flagged as the “analyzed record” will also be listed in subject listings. 
Table 3 
Visit Window 
Scheduled Visit/Period 
Scheduled Visit Day   
Analysis Visit Window 
Visit 1 & 2/Screening  
 
Any Day up to -2 
Visit 3/Baseline 
Day -1 
Day -1 
Visit 4/Treatment 1 
Day 7 
Day  1 – 7 
Visit 5/Treatment 2 
Day 14 
Day  8 – 14 
Visit 6/Follow-up 
Day 21 
Day 15 or later 
5.4.5.
Multiple Assessments 
For the multiple assessments at Baseline visit, refer to Section 5.3 for the Baseline definition. For 
handling the multiple visits within an analysis visit window, refer to Section 5.4.4. 
5.5.
Handling of Missing Data 
Missing data for the efficacy endpoints will not be imputed. Missing or partially missing prior or 
concomitant medications (Section 8.4 and 8.5) and AEs start and stop dates (Section 10.2) will 
be handled as specified in each section. 
 
 


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6.
STUDY POPULATION 
6.1.
Subjects Disposition 
The numbers and percentages of subjects completing the study and discontinuing from the study 
with reason and treatment period for termination will be presented. 
6.2.
Screen Failures 
A listing of all screening failure patients will be produced. 
6.3.
Protocol Deviations 
The major Protocol Deviations will be summarized. A supporting data listing will be provided. 
6.4.
Demographic and Baseline Characteristics 
Subject demographics and baseline data (race, ethnicity, sex, age, weight at screening, height and 
body mass index [BMI]) will be summarized by treatment sequence (Placebo/JZP-110, JZP-110 
/Placebo and Total) for each analysis population. Race, ethnicity, and sex will be summarized by 
frequency and percentage of subjects. The denominators for calculating the percentages will be 
the number of subjects in each analysis population. Age, weight (at screening), height and BMI 
will be summarized using descriptive statistics including the number of subjects, mean, median, 
standard deviation (SD), minimum and maximum.  
6.5.
Medical History 
Medical/surgical history collected at screening and Baseline will not be coded. Medical/surgical 
history data will be listed by reported term. 
Narcolepsy specific medical history will be summarized by treatment sequence. 
 


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7.
EFFICACY  
7.1.
General Considerations 
Observed data and difference between Placebo and JZP-110 at each scheduled visit will be 
summarized by treatment group (Placebo, JZP-110). For categorical data, frequency counts and 
percentages will be presented in a similar manner. 
7.2.
Statement of the Null and Alternate Hypotheses 
The statistical null hypothesis for the primary efficacy analysis is that the mean in SDLP at 2 
hours post-dose for the JZP-110group is equal to the mean in SDLP for the Placebo group. The 
alternative hypothesis is that the mean SDLP at 2 hours post-dose for JZP-110 group is not equal 
to that for the Placebo group. The treatment difference in mean SDLP between JZP-110 and 
placebo at 2 hours post-dose will be tested. A 5% type I error rate with a 2-sided p-value less 
than 0.05 will be considered as statistically significant. 
7.3.
Subgroup Analyses 
No subgroup analyses will be conducted in the study. 
7.4.
Multiple Comparisons and Multiplicity 
No multiplicity adjustments will be made in the efficacy analyses for multiple endpoints. 
7.5.
Analysis of the Primary Efficacy Endpoint 
7.5.1.
Primary Efficacy Analysis 
The primary outcome measure of mean change in SDLP will be analyzed using a repeated mixed 
effect analysis of variance (ANOVA) model. The model will include treatment (JZP-110 and 
placebo), driving performance test (2 hours post-dose and 6 hours post-dose), treatment period, 
treatment sequence and treatment by driving performance test interaction as fixed effects and 
subject as a random effect. The 2-sided 95% CIs of JZP-110-Placebo changes for SDLP based on 
the repeated mixed effect ANOVA model will be constructed for each driving performance test. 
The treatment sequence will also be included in the model if the treatment sequence effect is 
significant. 
The assumption on normal distribution of the data required for ANOVA model will be examined 
using Shapiro-Wilk Normality test on the residuals from the mixed-effect model. Also the 
homogeneity of variance between treatments will be evaluated using the Levene test. If the 
normality assumption and/or the homogeneity assumption are not satisfied at a significance level 
of 0.05, non-parametric method (Wilcoxon Signed Rank test) will be used to compare the pair-
wise treatment differences. 
A 5% type I error rate with a 2-sided p-value less than 0.05 will be considered as statistically 
significant.  


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Following provides the SAS code for linear mixed model analysis that will be used to analyze 
SDLP: 
PROC MIXED; 
CLASS SEQ PATIENT PERIOD TRT TIME; 
MODEL SDLP = SEQ PERIOD TRT TIME TRT*TIME/dfm=kr; 
REPEATED TIME/TYPE=CS SUB=PERIOD*PATIENT (SEQ); 
RANDOM INTERCEPT /SUB=PATIENT (SEQ); 
LSMEANS TRT * TIME/ CL DIFF ALPHA=0.05; 
RUN: 
 
Where, 
SEQ = Treatment Sequence 1 or 2 
PATIENT = Subject ID 
PEIROD = Treatment Period 1 or 2 
TRT = JZP-110 or Placebo 
TIME = 2 hours post-dose or 6 hours post-dose 
SAS procedure PROC MIXED will be used to carry out this analysis. All available data will be included 
in the model. A compound symmetry (CS) covariance matrix will be used to model the correlation among 
repeated measurements. The relative Hessian convergence criterion will be used in the ANOVA model. 
Least square (LS) estimates of treatment differences and their 95% confidence intervals will be presented 
respectively. 
The primary analysis will be based on the mITT population. 
7.5.2.
Sensitivity Analyses of the Primary Efficacy Results 
For primary efficacy endpoints, the analysis will be conducted using the same statistical model 
as the primary analysis based on the PP population, instead of the mITT population. 
Another sensitivity analysis may be conducted to evaluate the potential impact of missing data. 
7.6.
Analysis of the Secondary Efficacy Endpoints 
7.6.1.
Secondary Efficacy Analysis of Continuous Endpoints 
The secondary outcome measures of SDS, Driving lapses will be analyzed using the same model 
for SDLP.  
The following provides the SAS code for linear mixed model analysis that will be used to 
analyze PVT: 
PROC MIXED; 
CLASS SEQ PATIENT PERIOD TRT TIME; 
MODEL PVT = SEQ PERIOD TRT TIME TRT*TIME /dfm=kr; 
REPEATED TIME/TYPE=CS SUB=PERIOD*PATIENT (SEQ); 
RANDOM INTERCEPT /SUB=PATIENT (SEQ); 
LSMEANS TRT * TIME/ CL DIFF ALPHA=0.05; 
RUN: 
 


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Where, 
PVT = PVT measures (lapses, mean reaction time, inverse reaction time) 
SEQ = Treatment Sequence 1 or 2 
PATIENT = Subject ID 
PEIROD = Treatment Period 1 or 2 
TRT = JZP-110 or Placebo 
TIME = 2 hours post-dose or 6 hours post-dose 
 
The following provides the SAS code for linear mixed model analysis that will be used to 
analyze THAT: 
PROC MIXED; 
CLASS SEQ PATIENT PERIOD TRT; 
MODEL THAT = SEQ PERIOD TRT/dfm=kr; 
REPEATED/TYPE=UN SUB=PATIENT(SEQ); 
LSMEANS TRT/ CL DIFF ALPHA=0.05; 
RUN: 
 
Where, 
SEQ = Treatment Sequence 1 or 2 
PATIENT = Subject ID 
PERIOD = Treatment Period 1 and 2 
TRT = JZP-110 or Placebo 
7.6.2.
Secondary Efficacy Analysis of Dichotomous Endpoints 
Individual changes (JZP-110 minus Placebo) in driving performance will be measured by SDLP 
at 2 hours and 6 hours post-dose. Individual improvement is defined as a decrease in SDLP 
below the negative value of threshold; individual impairment is defined as an increase in SDLP 
above the threshold or failure to complete the driving test due to sleepiness or subject related 
safety concerns. 
The Max McNemar symmetry analyses (Laska et al. 2012) will be used to detect an asymmetry 
in the distribution of the change in driving performance at 2 hours and 6 hours post-dose. The 
test will examine the differences in the proportions of impaired drivers and improved drivers 
following treatment using a generalized sign test over all relevant thresholds. A McNemar test 
statistic will be obtained at each threshold. If the maximum is larger than the critical value of 
Max McNemar test for the pre-specified sample size and significance level as shown in Table 6 
(Laska et al. 2012), the difference in the proportions of subjects with improved or impaired 
driving performance will be statistically significant. The threshold under which the maximum of 
McNemar test statistic is selected will also be reported.  
A single McNemar test will be presented under each of the thresholds 1.0, 1.5, 2.0, 2.5, 3.0, 3.5.  
The following provides the SAS code for the McNemar analysis that will be used to analyze 
proportion of subjects with improved or impaired driving:  
PROC FREQ; 
  TABLE IMPROVE*IMPAIR / AGREE EXPECTED NOROW NOCOL NOPERCENT; 


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By TIME; 
RUN; 
Where, 
IMPROVE = improved driving (0/1) for each subject at each threshold 
IMPAIR = impaired driving (0/1) for each subject at each threshold 
TIME = 2 hours post-dose or 6 hours post-dose 
7.7.
Analysis of the Other Efficacy Endpoints 
Spearman correlations will be explored between driving measures (SDLP) and each of PVT 
measures (lapses, mean reaction time, inverse reaction time). 
The following provides the SAS code for Spearman analysis that will be used to analyze 
correlation between driving and PVT measures: 
PROC CORR SPEARMAN; 
  VAR SDLP PVT; 
By TIME; 
RUN; 
 
Where,  
PVT = PVT measures (lapses, mean reaction time, inverse reaction time). 
Sleep, Activity, Fatigue and Task Effectiveness (SAFTE) modeling using data from PVT, sleep 
diary and Actigraphy will be generated by Institutes For Behavior Resources, Inc (Baltimore, 
MD). The analysis plan is documented separately from this SAP. PVT analyses specified in this 
SAP will be used to aid analyses in the SAFTE modeling. 
The variables from Actigraphy (Total Sleep Time, Wake Time after Sleep Onset (WASO), Sleep 
Period, Sleep Efficiency, Sleep Onset Latency for 24-hours and night sleep periods) derived 
from each treatment period and the change from Baseline will be summarized. The Baseline 
value will be derived from the average of measurements from 7 days before the first dosing. The 
post-baseline value will be the average of measurements collected in the treatment period. 


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8.
SAFTY AND TOLERABILITY 
8.1.
Overall Summary of Tolerability 
All safety analyses will be based on the safety population. 
8.2.
Adverse Events 
8.2.1.
Summaries of Adverse Event Incidence Rates for All Subjects 
Adverse events will be coded using MedDRA 18.0 to classify events under primary SOC and 
PT. 
A treatment-emergent adverse event (TEAE) is defined as an AE that either begins after the first 
dose of study drug or worsens after the first dose of study drug. Each TEAE will be attributed to 
the treatment assigned when it started. 
TEAEs will be summarized by SOC and PT and treatment assigned with sorting based on 
alphabetical order for the SOC and frequency count (descending order for Total) for the PT. In 
addition, the incidence of all TEAEs and serious TEAEs will be summarized by PT with sorting 
based on the frequency count (descending order). 
An overview of AEs will include the number and percent of subjects who had at least one TEAE, 
serious TEAE, TEAE related/suspected to be related to study drug, TEAE related/suspected to be 
related to study procedure, study drug withdrawn due to TEAE, maximum severity of TEAE, or 
TEAE with fatal outcome. 
Multiple occurrences of an AE are counted only once per subject per SOC and PT for summary 
tables. 
The following TEAEs will be summarized: 
-
Incidence of all TEAEs 
-
Incidence of all TEAEs by maximum severity (severe, moderate and mild)  
-
Incidence of TEAEs related/suspected to be related to study drug 
-
Incidence of TEAEs related/suspected to be related to study procedure 
-
Incidence of serious TEAEs 
-
Incidence of serious TEAEs related/suspected to be related to study drug 
-
Incidence of TEAEs leading to study drug interruption 
-
Incidence of TEAEs leading to study drug withdrawn and withdrawn from study 
-
Incidence of TEAEs in which the outcome is fatal 
-
Incidence of all TEAEs in Safety Follow-up period 
All data collected in the AE case report form (CRF) will also be listed in by-subject listings.   


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8.3.
Total Duration of Therapy and Compliance 
Exposure to study drug and study drug compliance will be summarized by treatment group. 
A listing by subject will be provided to include the following: 
x
Date, time (if onsite) , and study day of study drug administration 
x
Treatment, site (clinic or home) 
x
Dose number and any dosing issue or deviation will be provided. 
Drug accountability (dispensed or returned number of tablets) will be listed by subject. 
8.4.
Prior Medications 
Prior medications will be defined as medications with a start date prior to the first dose of study 
drug. The stop date of the medication should be before or after the first dose of study drug or the 
medication may be ongoing. If a start date is completely missing, then the medication will be 
considered a prior medication. 
Prior medications will be summarized by anatomical therapeutic chemical (ATC) level 3 term 
and preferred term based on the Safety population. 
8.5.
Concomitant Medications 
Concomitant medications will be defined as medications with a stop date on or after the first 
dose of study drug or any medication that is ongoing. The start date of the medication may be 
before or after the first dose of study drug. A medication with completely missing use dates or 
partially missing use dates without evidence that the medication was stopped prior to the first 
dose of study drug will be considered a concomitant medication. 
Concomitant medications will be summarized by ATC level 3 term, preferred term based on the 
Safety population. 
8.6.
Routine Laboratory Data 
The data collected at screening visit in hematology, serum chemistry and quantitative urinalysis 
test results will be provided in the listing. 
8.7.
Vital Signs 
Vital signs will include systolic and diastolic blood pressure (SBP and DBP), pulse rate (PR), 
respiratory rate and body temperature. For the vital signs obtained at Baseline, Visit 4, Visit 5 
and Visit 6 or Early Termination visit, the observed values and difference between Placebo and 
JZP-110 at each time point and the change from Baseline in each vital sign parameter to each 
post-baseline time point will be summarized by treatment group. 
The number and percentage of subjects with changes in PR, SBP and DBP from Baseline (and 
Visit 4) in blood pressure and heart rate to each post baseline time point in the following 
categories will be summarized:  
x
% of subjects with an increase in PR of ≥5, ≥10, ≥15 and ≥30   
x
% of subjects with a decrease in PR of ≥5 ≥10 ≥15 and ≥30   


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x
% of subjects with an increase in SBP of ≥5,  ≥10, ≥20, and ≥30 
x
% of subjects with a decrease in SBP of ≥5, ≥10, ≥20, and ≥30 
x
% of subjects with an increase in DBP of ≥5, ≥10, ≥20, and ≥30 
x
% of subjects with a decrease in DBP of ≥5, ≥10, ≥20, and ≥30 
Reference ranges for each vital sign parameter in Table 4 will be used to categorize the results as 
low (lower than the lower limit), within the reference range, or high (higher than the upper limit).  
In addition, shifts in categories from Baseline (and Visit 4) to each post-baseline time point for 
each parameter will be summarized by treatment group. 
Table 4 
Vital Sign Reference Range 
Parameter 
Lower Limitof Reference
Range 
Upper Limitof
ReferenceRange 
SystolicBloodPressure(mmHg) 
90
<140 
DiastolicBloodPressure(mmHg) 
60
<90 
HeartRate(beats/min) 
Female: 55, Male50
Female:95,Male90
RespirationRate(breaths/min) 
12
30 
8.8.
ECG 
Observed data at Screening in ECG parameters will be included in the listing. 
8.9.
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidal Ideation, Suicidal Behavior, and Self-Injurious Behavior without Suicidal Intent at each 
time point will be classified by C-SSRS outcomes and composite score. 
8.9.1.
C-SSRS Outcomes/Composite Scores 
The following C-SSRS outcomes have binary responses (yes/no).  
x
Suicidal Ideation (Categories 1 – 5) 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
x
Suicidal Behavior (Categories 6 – 10) 
6. Preparatory acts or behavior 
7. Aborted attempt 
8. Interrupted attempt 
9. Non-fatal suicide attempt 
10. Completed suicide 
x
Suicidal Ideation or Behavior (1-10) 
x
Self-injurious behavior without suicidal intent 
Composite endpoints based on the above categories are defined below:
x
Suicidal ideation:  A “yes” answer during treatment to any one of the five suicidal 
ideation questions (Categories 1-5) on the C-SSRS. 


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x
Suicidal behavior:  A “yes” answer during treatment to any one of the five suicidal 
behavior questions (Categories 6-10) on the C-SSRS. 
x
Suicidal ideation or behavior: A “yes” answer during treatment to any one of the 
ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
Composite scores based on the above categories are defined below: 
Suicidal Ideation score (0 to 5) is based on answers (Yes) to five suicidal ideation questions 
(Categories 1-5) on the C-SSRS: 
0 = No suicidal ideation 
1 = Wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Activity suicidal ideation with any methods (not plan) without intent to act 
4 = Activity suicidal ideation with some intent to act, without specific plan 
5 = Activity suicidal ideation with specific plan and intent 
Suicidal Behavior score (6 to 10) is based on answers (Yes) to the five suicidal behavior 
questions (Categories 6-10) on the C-SSRS: 
0 = No suicidal behavior 
6 = Preparatory acts or behavior 
7 = Aborted attempt 
8 = Interrupted attempt 
9 = Non-fatal suicide attempt  
10 = Completed suicide 
Suicidal Ideation or Behavior score (0 to 10) is based on answers (Yes) to the ten suicidal 
ideation and behavior questions (Categories 1-10) on the C-SSRS. 
8.9.2.
C-SSRS Analyses 
A listing of subjects with Suicidal Ideation, Suicidal Behavior, or self-injurious behavior without 
suicidal intent based on the C-SSRS at each time point will be provided. 
 
 
 


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9.
REFERENCE LIST 
Ramaekers JG, Kuypers KP, Samyn N. Stimulant effects of 3,4-
methylenedioxymethamphetamine (MDMA) 75 mg and methylphenidate 20 mg on actual 
driving during intoxication and withdrawal. Addiction. 2006; 101: 1614-21. 
 
Verster JC, Bekker EM, de Roos M. Methylphenidate significantly improves driving 
performance of adults with attention-deficit hyperactivity disorder: a randomized crossover trial. 
J Clin Psychopharmacol. 2008; 22: 230-37.  
 
Laska E, Meisner M, Wanderling J. A maximally selected test of symmetry about zero. Stat 
Med. 2012: 31 (26): 3178-91. 
 


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10.
APPENDIX 
10.1.
10.1 Additional reference tables 
Table 5 
Schedule of Events 
  
 


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Table 6 
Critical Values of Max McNemar Test for Sample Size K = 8 to 99, 
Significance level α = 0.1, 0.05, 0.025 and 0.01. 
 
 
 


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10.2.
Date Imputation Rules 
Incomplete Adverse Event Onset Date 
If year is missing (or completely missing): set to the date of first dose. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
 
If year = year of first dose: set the date to the first dose date. 
 
If year < year of first dose: set month and day to December 31st. 
 
If year > year of first dose: set month and day to January 1st. 
If month and year are present and day is missing: 
 
If year = year of first dose, and: 
If month = month of first dose: set day to day of first dose. 
 
 
If month < month of first dose: set day to last day of month. 
 
 
If month > month of first dose: set day to 1st day of month. 
 
If year < year of first dose: set day to last day of month. 
 
If year > year of first dose: set day to 1st day of month. 
             For all other cases: set to date of first dose. 
 
Incomplete Concomitant Medication Start Date 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
Set month and day to January 1st. 
If year and month are present and day is missing: 
Set day to 1st day of month.  
 
Incomplete Concomitant Medication End Date 
Do not impute if Ongoing Flag is checked. 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
Set month and day to December 31st. 


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If year and month are present and day is missing: 
Set day to last day of the month.