Clinical trial NCT03141086
Conditions: Circadian Rhythm Disorders
Keywords: shift work disorder
Sponsor: Novartis Pharmaceuticals
Start date: 2017-07-26; Completion date: 2018-09-12
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study was to demonstrate that LML134 can increase wakefulness compared to placebo in patients with shift work disorder (SWD) measured by objective and subjective endpoints of wakefulness, i.e. the sleep latency in the multiple sleep latency test (MSLT) and the Karolinska Sleepiness Scale (KSS), respectively. Safety and PK of LML134 were also evaluated. In addition, novel methodologies to measure wakefulness and sleep were also to be tested and compared to gold standard methods like the MSLT and polysomnography (PSG) (at sites where staff have appropriate equipment and training). The aim of such comparisons was to evaluate the usefulness of the new technologies in clinical studies and provide preliminary validation data.

This was a randomized, subject and investigator-blinded, placebo controlled, crossover, multi-center Proof of Concept (PoC) study with in-house simulated laboratory night shifts in patients with SWD. This non-confirmatory study included two treatment arms: LML134 and placebo. After a screening period, the treatment phase of the study consisted of two overnight stays in a sleep lab in each of two treatment periods, with a minimum one week wash-out in between.

Detailed description:

Arms: arm 1: LML134, then placebo arm 2: Placebo, then LML134
Interventions: intervention 1: LML134 intervention 2: Placebo
Intervention descriptions: intervention 1: LML134 intervention 2: placebo

Protocol documents:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LML134
Clinical Trial Protocol CLML134X2201
A randomized, subject and investigator-blinded, placebo 
controlled, cross-over, multi-center Proof of Concept (PoC) 
study to assess the wakefulness promoting effect, safety, 
tolerability, and pharmacokinetics of LML134 in shift work 
disorder (SWD) patients
Document type:
Amended Protocol Version
EUDRACT number:
N/A
Version number:
v04 (Clean)
Clinical Trial Phase:
Phase II
Release date:
09-May-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO& PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................24
1
Introduction .......................................................................................................................27
1.1
Background............................................................................................................27
1.4
Study purpose ........................................................................................................32
2
Objectives and endpoints...................................................................................................32
2.1
Primary objective(s)...............................................................................................32
3
Investigational plan ...........................................................................................................34
3.1
Study design...........................................................................................................34
3.2
Rationale of study design.......................................................................................37
3.3
Rationale for dose/regimen, route of administration and duration of treatment....39
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3.4
Rationale for choice of comparator .......................................................................40
3.6
Risks and benefits..................................................................................................41
3.6.1
Blood sample volumes..........................................................................44
4
Population..........................................................................................................................44
4.1
Inclusion criteria ....................................................................................................44
4.2
Exclusion criteria...................................................................................................45
5
Restrictions for Study Subjects .........................................................................................49
5.1
Contraception requirements...................................................................................49
5.2
Prohibited treatment...............................................................................................50
5.3
Dietary restrictions and smoking...........................................................................51
5.4
Other restrictions ...................................................................................................52
6
Treatment...........................................................................................................................52
6.1
Study treatment......................................................................................................52
6.1.1
Investigational treatment and control drug(s) .......................................52
6.1.2
Additional study treatment....................................................................52
6.2
Treatment arms......................................................................................................52
6.3
Treatment assignment and randomization.............................................................53
6.4
Treatment blinding.................................................................................................53
6.5
Treating the subject................................................................................................55
6.6
Permitted dose adjustments and interruptions of study treatment.........................55
6.7
Emergency breaking of assigned treatment code ..................................................55
6.8
Treatment exposure and compliance .....................................................................56
6.9
Recommended treatment of adverse events ..........................................................56
6.10
Rescue medication.................................................................................................56
6.11
Concomitant treatment...........................................................................................56
7
Study completion and discontinuation ..............................................................................57
7.1
Study completion and post-study treatment ..........................................................57
7.2
Discontinuation of study treatment........................................................................57
7.3
Withdrawal of informed consent ...........................................................................59
7.4
Lost to follow-up ...................................................................................................59
7.5
Study Stopping rules..............................................................................................60
7.6
Early study termination by the sponsor .................................................................60
8
Procedures and assessments ..............................................................................................61
8.1
Assessment schedule .............................................................................................61
8.2
Informed consent procedures.................................................................................70
8.3
Subject screening...................................................................................................71
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8.4
Subject demographics/other baseline characteristics.............................................71
8.4.1
Hepatitis and HIV Screen......................................................................71
8.4.2
Alcohol Test, Drug Screen, and Cotinine Test .....................................71
8.4.3
STOP-BANG questionnaire..................................................................71
8.5
Efficacy / Pharmacodynamics ...............................................................................72
8.5.1
MSLT....................................................................................................72
8.5.2
Clinical Outcome Assessments (COAs) ...............................................72
8.6
Safety.....................................................................................................................73
8.6.1
Physical Examination............................................................................73
8.6.2
Vital signs..............................................................................................73
8.6.3
Height and weight .................................................................................73
8.6.4
Laboratory evaluations..........................................................................74
8.6.5
ECG evaluation.....................................................................................74
8.6.6
Pregnancy and assessments of fertility .................................................75
8.6.7
Polysomnography..................................................................................75
8.6.8
Neurological Examination ....................................................................75
8.7
Pharmacokinetics...................................................................................................76
9
Safety monitoring ..............................................................................................................77
9.1
Adverse events.......................................................................................................77
9.2
Serious adverse event reporting.............................................................................79
9.2.1
Definition of SAE .................................................................................79
9.2.2
SAE reporting........................................................................................80
9.3
Liver safety monitoring .........................................................................................81
9.4
Renal safety monitoring.........................................................................................82
9.5
Reporting of study treatment errors including misuse/abuse ................................82
9.6
Pregnancy reporting...............................................................................................83
9.7
Prospective suicidality assessment ........................................................................84
9.8
Early phase safety monitoring ...............................................................................84
10 Data review and database management.............................................................................85
10.1
Site monitoring ......................................................................................................85
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10.2
Data collection.......................................................................................................85
10.3
Database management and quality control............................................................86
10.4
Data Monitoring Committee..................................................................................86
10.5
Adjudication Committee........................................................................................86
11 Data analysis......................................................................................................................87
11.1
Analysis sets ..........................................................................................................87
11.2
Subject demographics and other baseline characteristics......................................87
11.3
Treatments .............................................................................................................87
11.4
Analysis of the primary variable(s) .......................................................................87
11.4.1
Primary Variable(s)...............................................................................87
11.4.2
Statistical model, hypothesis, and method of analysis..........................87
11.4.3
Handling of missing values/censoring/discontinuations.......................88
11.4.4
Sensitivity analyses ...............................................................................89
11.4.5
Supportive analysis ...............................................................................89
11.5
Analysis of secondary variable(s)..........................................................................89
11.5.1
Efficacy / Pharmacodynamics...............................................................89
11.5.2
Safety.....................................................................................................90
11.5.3
Pharmacokinetics ..................................................................................91
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................91
11.5.5
Other assessments .................................................................................91
11.7
Sample size calculation..........................................................................................93
12 Ethical considerations........................................................................................................94
12.1
Regulatory and ethical compliance........................................................................94
12.2
Responsibilities of the investigator and IRB/IEC..................................................94
12.3
Publication of study protocol and results...............................................................95
12.4
Quality Control and Quality Assurance.................................................................95
13 Protocol adherence ............................................................................................................95
13.1
Protocol Amendments ...........................................................................................96
14 References .........................................................................................................................97
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................99
16 Appendix 2: Specific Renal Alert Criteria and Actions..................................................101
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Table 5-1
Prohibited medication ...........................................................................50
Table 6-1
Overview of study medication ..............................................................52
Table 6-2
Definition of treatment sequences.........................................................52
Table 6-3
Treatment Assignment Numbering.......................................................53
Table 6-4
Blinding and unblinding plan................................................................55
Table 8-1
Assessment schedule.............................................................................61
Table 9-1
Guidance for capturing study treatment errors......................................83
Table 11-1
Operating characteristics for dual criteria.............................................93
Table 15-1
Liver Event Definitions.........................................................................99
Table 15-2
Actions required for Liver Events.........................................................99
Table 15-3
Exclusion of underlying liver disease .................................................100
Table 16-1
Specific Renal Alert Criteria and Actions...........................................101
Table 16-2
Follow-up of renal events....................................................................102
List of figures
Figure 3-1
Study design..........................................................................................34
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List of abbreviations
ACR
Albumin-creatinine ratio 
AE
adverse event
AHI
apnea-hypopnea index 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time 
AST
aspartate aminotransferase
BMI
Body Mass Index
BP
blood pressure
BUN
blood urea nitrogen
C-SSRS
Columbia Suicide Severity Rating Scale
CFR
U.S. Code of Federal Regulation
CGI-S
Clinical Global Impression-Severity 
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
COA
Clinical Outcome Assessments 
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSF
cerebrospinal fluid 
CV
coefficient of variation
DDE
Direct Data Entry 
ECDEU
Early Clinical Drug Evaluation Program 
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency 
ES
excessive sleepiness
eSource
Electronic Source
FIH
First-in-human 
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GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
H3R
H3 receptors 
HA
histamine
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HV
healthy volunteers 
IB
Investigator's Brochure 
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notifications
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LLN
lower limit of normal
LLOQ
lower limit of quantification
MAD
Multiple Ascending Dose 
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MSLT
Multiple Sleep Latency Test 
NIRT
Novartis Interactive Response Technology
PA
posteroanterior
PCR
Protein-creatinine ratio 
PD
pharmacodynamic(s)
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PET
positron emission tomography
PK
pharmacokinetic(s)
PLMSArI
periodic leg movement in sleep with arousal index 
PoC
Proof of Concept
PoP-PK
Population Pharmacokinetics
PRO
Patient Reported Outcomes 
PSG
polysomnography
PT
prothrombin time
QM
Quality Management 
QTcF
Fridericia QT correction formula 
RBC
red blood cell(s)
REM
rapid eye movement
RO
receptor occupancy 
SAD
Single Ascending Dose 
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
SWD
shift work disorder 
TBL
total bilirubin
tMeHA
tele-methylhistamine 
TMN
tuberomammillary nucleus 
TSH
thyroid stimulating hormone 
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to time 't' where t is a defined time point after administration 
[mass x time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x time 
/ volume]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau [mass x time / volume]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
T1/2
The terminal elimination half-life [time]
Tmax
The time to reach the maximum concentration after drug administration 
[time]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested in 
the trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Electronic 
Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in 
the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource combines source 
documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication 
pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest


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Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to subject’s medications 
or other intervention)
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants 
as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study 
treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


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Protocol summary
Protocol number
CLML134X2201
Full Title
A randomized, subject and investigator-blinded, placebo controlled, cross-over, 
multi-center Proof of Concept (PoC) study to assess the wakefulness 
promoting effect, safety, tolerability, and pharmacokinetics of LML134 in shift 
work disorder (SWD) patients
Brief title
A Proof of Concept (PoC) study to assess the wakefulness promoting effect of 
LML134 in shift work disorder patients
Sponsor and 
Clinical Trial Phase
Novartis
Phase II
Intervention type
Drug 
Study type
Interventional
Purpose and 
rationale
The main purpose of this study is to demonstrate that LML134 can increase 
wakefulness compared to placebo in patients with shift work disorder (SWD) 
measured by objective and subjective endpoints of wakefulness, i.e. the sleep 
latency in the multiple sleep latency test (MSLT) 
 
Safety and PK of LML134 will also be evaluated. 
 
 
 
 
Primary 
Objective(s)
To demonstrate that wakefulness in SWD patients is significantly increased 
after treatment with LML134 compared to placebo 
Secondary 
Objectives
To assess the safety and tolerability of LML134 compared to placebo in SWD 
patients
To assess the plasma pharmacokinetics of LML134 in SWD patients
To evaluate the time course of LML134 effect on wakefulness compared to 
placebo
Study design
This is a randomized, subject and investigator-blinded, placebo controlled, 
crossover, multi-center Proof of Concept (PoC) study with in-house simulated 
laboratory night shifts in patients with SWD. This non-confirmatory study will 
include two treatment arms: LML134 and placebo. After a screening period, the 
treatment phase of the study will consist of two overnight stays in a sleep lab in 
each of two treatment periods, with a minimum one week wash-out in between.
After each treatment period the subjects will return for a safety follow-up visit.
Population
The study population will be comprised of patients with SWD. Specifically, 
these will be night shift workers.
A total of approximately 46 men and women aged 18 to 65 years will be 
enrolled in the study and randomized. 
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Key Inclusion 
criteria
!
Male and female subjects18 to 65 years of age included.
!
Confirmed diagnosis of SWD according to ICSD-3 criteria at Screening.
!
Subjects who are at least moderately ill with respect to sleepiness on work 
nights, including commute to and from work, as assessed by the Clinical 
Global Impression-Severity scale (CGI-S, score ≥4) at Screening.
!
Subjects must work 5 or more night shifts per month, and 2 or more shifts 
must occur on consecutive nights, with 6 or more hours worked between 
10 pm and 8 am, as confirmed by subject at Screening.
!
Subjects must have mean sleep latency ≤8 minutes on nighttime MSLT at 
Screening.
!
Subjects must weigh at least 50 kg at Screening to participate in the study, 
and must have a body mass index (BMI) within the range of 18 - 35 kg/m2. 
BMI = Body weight (kg) / [Height (m)]2
Key Exclusion 
criteria
!
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are willing to use highly 
effective contraception and an additional barrier method for the required 
period. Sexually active males unwilling to use a condom during intercourse 
while taking investigational drug and for 3 days after stopping 
investigational drug. A condom is required for all sexually active male 
participants to prevent them from fathering a child AND to prevent delivery 
of the investigational drug via seminal fluid to their partner.
!
Subjects, for whom it is not safe to discontinue or who are unwilling to 
discontinue use of modafinil, hypnotics, and antihistamines for the periods 
specified in the prohibited medication section.
!
Heavy caffeine consumers, i.e. subjects who consume greater than 
850 mg of caffeine per day (approximate equivalent of three tall cups of 
Starbucks coffee) in coffee, tea, or other caffeine-containing drinks.
!
Subjects who have high risk of obstructive sleep apnea, indicated by score 
of 5 or more on the STOP-BANG questionnaire.
!
Presence of any sleep disorder other than SWD, as confirmed by PSG at 
screening.
Study treatment
!
LML134
!
Placebo
Pharmacokinetic 
assessments
!
Population PK model
Efficacy/PD 
assessments
!
MSLT
Key safety 
assessments
!
Adverse event monitoring
!
Physical examinations
!
Monitoring of laboratory markers in blood and urine
!
ECG
!
Polysomnography
Other assessments
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Data analysis
Mean sleep latency score data will be analyzed using a mixed effect ANOVA 
model with treatment and period as fixed effects and subject as a random 
effect. Least square estimates for each treatment and treatment difference 
(LML134 vs placebo) along with 95% confidence interval will be reported.
Key words
Shift work disorder, multiple sleep latency test, sleep, polysomnography


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1
Introduction
1.1
Background
Shift work disorder (SWD) is a common yet under-recognized and undertreated circadian 
rhythm sleep disorder. It is caused by a misalignment between the patient's endogenous 
circadian rhythm and the sleep-wake pattern dictated by the environment. The two prevailing 
symptoms of SWD are insomnia and excessive sleepiness (ES). The symptoms are associated 
with shift work that happens, at least in part, during the usual hours of the main sleep episode. 
SWD occurs despite the patients' attempts to optimize environmental conditions for sleep. 
The condition usually persists only for the duration of the shift work schedule, but in some 
individuals, the sleep disturbance may persist beyond the duration of shift work 
(AASM 2014). SWD has been estimated to affect 10-23% of the approximately 22 million 
shift workers in the US, which translates into a 2-5% prevalence in the general population
(Schwartz and Roth 2006). Patients with SWD report greater mood problems, such as 
impatience, avoidance of interaction with coworkers, a higher risk of depression, impaired 
social functioning, and lower coping skills. Patients with SWD also have a higher risk of 
subjective health complaints, ulcers, and substance abuse. Importantly, the ES and fatigue 
experienced by SWD patients often causes performance impairment and diminished 
attentiveness leading to higher risk of accidents both during work and during commute 
between work and home (Ohayon et al 2002; Folkard and Tucker 2003; Barger et al 2005).
Modafinil is approved in the US for the treatment of ES in SWD, but its efficacy is perceived 
as modest (Czeisler et al 2005). Moreover, modafinil is associated with increased risk of skin 
and other hypersensitivity reactions, cardiovascular and neuropsychiatric disorders, which led 
to the withdrawal of the European marketing authorizations in all indications except for 
narcolepsy due to an unfavourable benefit-risk assessment EMA (2010).
The histaminergic system is one of the key wake-promoting systems in the brain. 
Histaminergic neurons are located in the tuberomammillary nucleus (TMN) and fire actively 
during wakefulness, less frequently during sleep and completely cease firing during rapid eye 
movement (REM) sleep (Lin et al 2011). Firing rate of histaminergic neurons and histamine 
(HA) release are regulated by presynaptic H3 receptors (H3R). H3R are Gi/Go-protein 
coupled receptors with high constitutive activity that inhibit TMN neuron firing and HA 
release under basal conditions and through activation by HA (Benarroch 2010). 
Inverse agonists can decrease the constitutive activity of H3R and thereby increase the release 
of HA in brain leading to increased wakefulness.
Recently, H3R inverse agonists have been evaluated as a potential treatment for ES and 
cognitive impairment. The first drug, pitolisant (Wakix™) has been approved by the 
European Medicines Agency (EMA) for the treatment of narcolepsy in 2016. However, the 
clinical utility of H3R inverse agonists is limited by their major side effect, insomnia, arising 
from prolonged duration of action. This major side effect might restrict the dose tolerated by 
patients, and thereby lead to limited efficacy.


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The most relevant data for the present study are summarized in the sections below. For 
detailed information, please refer to the Investigator's Brochure.
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1.4
Study purpose
The main purpose of this study is to demonstrate that LML134 can increase wakefulness 
compared to placebo in patients with SWD measured by objective and subjective endpoints of 
wakefulness, i.e. the sleep latency in the multiple sleep latency test (MSLT) 
 
Safety, tolerability and PK of LML134 will 
also be evaluated in SWD patients. The study is expected to provide information on whether 
the overall clinical profile of the drug warrants further clinical development in this indication.
2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary 
objective(s)
!
To demonstrate that wakefulness in SWD patients 
is significantly increased after treatment with 
LML134 compared to placebo 
!
Average sleep latency over two 
consecutive test nights as 
measured by the MSLT
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)
!
To assess the safety and 
tolerability of LML134 
compared to placebo in SWD 
patients
!
Standard safety assessments such as vital signs, ECG, 
hematology, blood chemistry, urinalysis, AE 
reporting, and daytime PSG to assess drug effect on 
sleep
!
To assess the plasma 
pharmacokinetics of LML134 
in SWD patients
!
Due to sparse sampling, only plasma concentrations 
will be listed and no PK parameter will be evaluated 
by noncompartmental analysis. The data will be part 
of the overall Population PK model
!
To evaluate the time course 
of LML134 effect on 
wakefulness compared to 
placebo 
!
MSLT at each time point averaged over two 
consecutive test nights
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3
Investigational plan
3.1
Study design
This is a randomized, subject and investigator-blinded, placebo controlled, crossover, 
multi-center Proof of Concept (PoC) study with in-house simulated laboratory night shifts in 
patients with SWD. This non-confirmatory study will include two treatment arms: LML134 
 and placebo.
The study will utilize a 2x2 crossover design, with two treatment periods and two sequences 
as shown in Figure 3-1. Approximately 46 subjects will be randomized in this study. 
All subjects will receive both treatments (LML134 and placebo), one in each treatment period, 
with the order of treatment being randomized.
Figure 3-1
Study design
*Second Baseline can be delayed to accommodate a washout period of up to 5 weeks between 
the last dose in Treatment period 1 and the first dose in Treatment period 2.
An initial screening period will include screening for eligibility including a clinical interview 
and collection of at least two weeks (14 days) of outpatient paper sleep diary to confirm SWD 
diagnosis according to ICSD-3 criteria. Subsequently, daytime sleep PSG and nighttime 
MSLT will be performed in the sleep lab on consecutive days that follow at least 
3 consecutive nights awake by the subject to exclude any other sleep disorder and estimate the 
severity of objective sleepiness, respectively. Timing of screening MSLT naps will 
correspond to the timing of efficacy MSLT (see assessment table for timing of highly
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A baseline prior to each treatment period will include an outpatient day visit to perform a 
variety of baseline assessments as specified in the assessment schedule. The baseline periods 
will be timed such that the patient completes at least 3 consecutive nights awake 
(corresponding to their regular shift work schedule) directly prior to coming in to begin the 
treatment period. The patients will also need to fill out the paper sleep diary during the 3 days 
before the treatment period. The outpatient baseline visit can take place on any day from 
day -7 to day -1, however results of the baseline assessments (including safety labs and drug 
screen) must be available before dosing.
If a patient needs to repeat baseline assessments then a repeat baseline visit can be performed 
following approval by the sponsor as long as the visit can be performed within the screening 
window (for baseline 1) or wash-out window (for baseline 2).
During screening and baseline (1 or 2) the required three consecutive nights awake can either 
include three consecutive working nights shifts in the patients regular work environment or 
two consecutive working nights shifts in the patients regular work environment and one 
additional night awake domiciled in the sleep lab. This additional night spent in the sleep lab 
may occur immediately prior to or after the patients scheduled work shifts and must follow 
the same schedule as a usual working night shift.  Documentation of any additional nights 
spend in the sleep lab must be documented in the sites source records. The patients will be 
supervised during the additional night at the sleep lab to avoid napping. Patients may choose 
to take their daytime sleep at the laboratory following the additional night spent there or may 
leave the center in the morning. In the latter case, they will be provided with safe transport 
home. If scheduling permits the patients can remain at the site to begin the treatment period
Day 1.
Each treatment period will be comprised of two nights of treatment and concomitant 
assessments and one day of recovery sleep in between (Day 2). Staying at the study center for 
recovery sleep on Day 3 is optional. Assessments will be identical in both treatment periods. 
After at least three consecutive nights awake following a night shift work schedule (during the 
baseline period), subjects will begin their daytime period of sleep (Day 1) starting at 
approximately 10:00 at the sleep laboratory clinical site. Total time spent in bed on Day 1 
should be approximately 8 hours. No sleep assessments are performed on Day 1, but other 
baseline assessments are performed as specified in the Assessment schedule.
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 On Night 1, safety assessments, 
 
 will be performed after daytime sleep but before dosing. 
If timing of the daytime sleep period would not allow completion of all necessary assessments 
before dosing, the physical and neurological exams, CSSR-S and alcohol/drug/cotinine screen 
can be completed before the subject goes to sleep in the morning. The subjects will receive 
the first dose of assigned drug at approximately 22:00, and will then perform a series of 
assessments repeated at regular intervals throughout the night. Wakefulness will be assessed 
using 
 the MSLT at approximately 1:30, 3:30, 5:30 and 7:30. 
 
 Subjects are not allowed to nap during the assessment nights 
outside the MSLT exams. They will be continuously supervised by site personnel to make 
sure they stay awake during the test nights.
Subjects will remain in the clinic for recovery sleep during Day 2 starting in the morning at 
approximately 10:00, and will undergo PSG to assess daytime sleep. Total time spent in bed 
on Day 2 should be approximately 8 hours.
 
 Subjects will also be requested to fill out a 
sleep diary upon waking on the days specified in the Assessment schedule.
Safety assessments, 
 will be performed again after 
daytime sleep but before dosing on Day 2, similarly to Day 1. Subjects will receive the second 
dose of assigned drug at approximately 22:00 on Night 2. Night 2 assessments will be 
identical to those completed on Night 1 at approximately the same clock time. 
 
 
Once all assessments on the morning of Day 3 have been completed, subjects 
can either remain in the clinic for Day 3 recovery sleep, or will be provided with safe 
transportation home for recovery sleep, if all safety assessments have been completed with 
satisfactory results.
Subjects will return to the clinical site for a follow-up visit for safety purposes 7 to 14 days 
after completion of treatment in both periods. The safety follow-up visit after the first period 
can also serve as baseline visit for the second period, if Treatment period 2 Day 1 occurs 
within 7 days of the visit. Sparse PK sampling will be done over the two day study period as 
indicated in the Assessment schedule to obtain an optimal exposure estimation with the help 
of the established Pop-PK model. 
Treatment periods will be separated by a wash-out of period of up to 5 weeks, depending on 
each subject's night shift work schedule. This washout should be measured from the last dose 
in treatment period 1 and the first dose in Treatment period 2. After both treatment periods 
have been completed and the follow-up safety visits have been completed subjects will 
undergo End Of Study evaluations and will be discharged from the study.
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If subjects discontinue early they should complete the EOS assessments before leaving the 
sleep lab and return within 7 to 14 days to complete the safety follow-up visit. (unless the 
subject withdraws the informed consent, see Section 7.3 for details).
3.2
Rationale of study design
Overall study design:
A cross-over study is planned to minimize the number of subjects and control for intra-subject 
variability during treatment comparison. The use of a subject and investigator-blinded placebo 
arm is to provide a comparison group for an unbiased collection of efficacy, safety, and 
tolerability data.
The purpose of the relatively long screening period is to allow time to establish the diagnosis 
of SWD according to ICSD-3 criteria, which requires assessment of the subject's circadian 
rhythm over a period of at least two weeks to demonstrate a disturbed sleep and wake pattern 
determined by a clinical interview and sleep diary data.
During the baseline period, each subject's circadian rhythm needs to be evaluated again with 
sleep diary data (which provides parameters such as total sleep time, time of going to bed and 
time of getting out of bed). This is necessary to inform about the subject’s sleep-wake cycles 
for both treatment periods, as MSLT results can be substantially influenced by duration and 
quality of sleep before the assessment. 
Subjects are required to stay at the sleep center for the entire treatment period, as the primary 
readout (MSLT) can only be performed at specialized centers.
Choice and timing of efficacy assessments:
The MSLT, which is considered the gold-standard objective measure of sleepiness, was 
selected as the primary readout to demonstrate the wakefulness promoting effect of LML134. 
It has successfully been used in previous studies in SWD patients to demonstrate drug effect 
on sleepiness.
 
 
 
 
Congruous to the timing of excessive sleepiness in SWD patients, all efficacy assessments 
will be performed during the night.
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Wakefulness 
 will be assessed at regular intervals during the treatment nights, as 
recommended by relevant guidelines (Littner et al 2005) and also performed in other studies 
in SWD patients (Czeisler et al 2005; Czeisler et al 2009). MSLT 
 will be 
timed such that they cover most of the regular interval corresponding to night shifts and the 
commute home (22:00 to 8:00), as this is the period when SWD patients could benefit from 
the effect of a wakefulness promoting drug. However, 
 and MSLT will not be 
performed during the earliest hours of the shift, as no substantial impairment is expected then.
Safety assessments:
 
 
 
 Therefore safety assessments in the present study will be 
limited to routine monitoring of vitals, ECG, selected lab parameters, brief neurological 
examination, and AE collection.
LML134 effect on sleep will also be evaluated using PSG as part of the safety assessments. 
LML134 is expected to promote wakefulness during the night shift without having a clinically 
significant effect on daytime sleep in SWD patients. PSG is considered the gold standard 
method to assess sleep. 
 
 
 
 
 
Selection of patient population:
Moderately or severely ill patients with ES during the night shift will be enrolled into the 
study, based on their CGI-S score on sleepiness and MSLT sleep latency. These are the 
patients who might benefit most from any wakefulness promoting drug. Previous studies with 
modafinil also recruited patients with similar characteristics.
Sparse PK sampling:
Sparse PK sampling will be done as indicated in the Assessment schedule to obtain an optimal 
exposure estimation with the help of the established Pop-PK (Population Pharmacokinetics) 
model. PK (LML134) and PD (sleep duration overnight) data from a Phase I Clinical Study 
were used for model development. Based on the developed PK model, the optimal 
experimental design theory was implemented to select the sampling times that would yield the 
maximum information (Aarons and Ogungbenro 2010). Based on the available resources, the
study design is required to meet the following criteria:
!
Number of PK samplings should be limited to 7
!
Sampling time window should be limited to 36 hours
!
Number of subjects should be 46 (2x2 cross-over design)
!
Dose amount should be assumed equal 
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The calculated optimal sampling times are: predose, 0.25, 2, 3, 12, 24, and 34.5 hours post 
first dose in each period. By using these sampling times, the PoC study results will allow for 
accurately (standard error < 50%) estimating all the PK model parameters (but Vperipheral) for 
the subjects. Only a longer time window, and not additional sampling time points, could 
decrease the high uncertainty in estimating Vperipheral. Given that a longer time window is not 
feasible, due to the inconvenience that would cause to the subjects, the aforementioned 
sampling times were finally selected for this study design.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Treatment duration
In each treatment period, subjects will receive the study drug on two consecutive nights. H3R 
inverse agonists, like LML134, rapidly increase histamine release in the brain after 
administration. 
 
 
 It is therefore expected that a single dose of LML134 will have 
wakefulness promoting effects and a single administration of the drug would be enough to 
assess its efficacy. Clinical studies with other H3R inverse agonists have verified that a single 
dose of the compound can indeed promote wakefulness and prolong sleep latency
(Iannone et al 2010).
The variability of MSLT sleep latency is large, particularly in multi-center studies. Therefore 
two nights of treatment are planned in the present study to allow calculation of mean sleep 
latency over the two-night period. The averaged readouts are expected to provide more robust 
results with lower variability than the single night readouts.
Treatment periods will be separated by a wash-out of 1-5 weeks, depending on each subject's 
night shift work schedule. Additionally, this washout period covers at least 5-times the 
half-life of LML134 (4.6 hours to 7.6 hours) to allow complete washout of LML134 from the 
body.
Dose of LML134 and time of administration
The dose of LML134 
 used in the present study is guided by results of the occupancy 
PET study and the PK/PD model based on the FIH study.
It is known from the literature (Iannone et al 2010)
 
that at least 80% of RO is needed to reach full efficacy of H3R inverse agonists. SWD 
patients could benefit from the wakefulness promoting effect of LML134 during the hours 
that correspond to the night shift (from 22:00 to 6:00) and during the additional hours that 
cover the usual time of commute to home (from 6:00 to 8:00). It is, however, also important to 
minimize the impact of LML134 on daytime sleep (starting at about 10:00) following the 
simulated night shift. Therefore the selected dose of LML134 is expected to provide full 
wakefulness promoting effect for the entire duration of the simulated shift but also minimize 
effect on daytime sleep duration.
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The main principle that guides selection of the LML134 dose is that RO should be sufficiently 
high to provide full efficacy during the entire simulated night shift. Therefore the dose of 
LML134 will be such that it is expected to provide >80% RO and thus full efficacy for about 
10 hours post dose in 90% of the subjects. 
 
 
 
 Thus study drug will be administered at 
approximately 22:00, at the beginning of the simulated night shift.
LML134 has a short half-life (4.6 hours to 7.6 hours). 
 
 
Thus accumulation of LML134 exposure is not expected to lead to a further 
reduction in total sleep time compared to the first post-dose sleep period.
3.4
Rationale for choice of comparator
The use of a placebo arm will provide a comparison group for an unbiased collection of 
efficacy, safety, and tolerability data. In most countries there is no regulatory approved 
treatment for excessive sleepiness in SWD, therefore placebo is an appropriate comparator.
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3.6
Risks and benefits
There is no benefit expected for subjects participating in this study.
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, in-patient setting, use of study-stopping rules, short duration of treatment, 
and assurance of safe transport home.
Following re-evaluation of safety data women of childbearing potential are eligible to 
participate in the study if they are willing to use highly effective contraception to prevent 
pregnancy, from start of the first treatment period until 3 days after the completion of the 
second treatment period and an additional barrier method while taking the study drug and for 
3 additional days in both treatment periods. There may be unknown risks of LML134 to an 
unborn human fetus or a nursing child that are not known and may be serious.
Sexually active males must be informed of the requirement to wear a condom for the 
following reasons:
!
Prevent pregnancy in a female partner
AND
!
Prevent  delivery of investigational drug via seminal fluid to their partner as study 
treatment may involve unknown risks to the fetus if pregnancy were to occur
There may be unknown risks of LML134 which may be serious.
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3.6.1
Blood sample volumes
A maximum of 500 mL of blood is planned to be collected from each subject as part of the 
study. The study has a maximum duration of around 18 weeks (including the maximum 
5 week washout period between treatment periods) . Additional samples may be required for 
safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Section 8.1).
A summary blood log is provided in the Site Operations Manual. Instructions for all sample 
collection, processing, storage and shipment information is also available in the SOM and 
central Laboratory Manual.
 
4
Population
SWD patients
The study population will be comprised of patients with SWD. Specifically, they will be night 
shift workers (permanent or rotating).
A total of approximately 46 subjects will be enrolled in the study and randomized. 
Replacement subjects may be enrolled to replace subjects who discontinue the study for 
reasons other than safety.
The Investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening 
and the relevant eligibility criteria at both baselines. A relevant record (e.g. checklist) of the 
eligibility criteria must be stored with the source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
4.1
Inclusion criteria
SWD patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female subjects 18 to 65 years of age included.
3. Diagnosis of SWD according to ICSD-3 criteria confirmed by a Clinical Interview at 
Screening supported by sleep diary results recorded for at least 2 weeks. Sleep diary 
results must be available at a minimum 4 days per week (during the 2 weeks of recording). 
4. Subjects who are at least moderately ill with respect to sleepiness on work nights, 
including commute to and from work, as assessed by the Clinical Global Impression-
Severity scale (CGI-S, score ≥4) at Screening.
5. Subjects must work 5 or more night shifts per month, and 2 or more shifts must occur on 
consecutive nights, with 6 or more hours worked between 10 pm and 8 am (22:00 and 
8:00), as confirmed by subject at Screening.
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6. Subjects must have mean sleep latency ≤8 minutes on nighttime MSLT at Screening.
7. Subjects must weigh at least 50 kg at Screening to participate in the study, and must have 
a body mass index (BMI) within the range of 18 - 35 kg/m2. BMI = Body weight (kg) / 
[Height (m)]2
8. At screening and each baseline, vital signs (systolic and diastolic blood pressure and pulse 
rate) will be assessed in the sitting position. Sitting vital signs should be within the 
following ranges:

oral body temperature between 35.0-38.0 °C

systolic blood pressure, 90-159 mmHg

diastolic blood pressure, 50-99 mmHg

pulse rate, 40-100 bpm
If vital signs are outside these ranges, the Investigator may obtain two additional readings, 
so that up to three consecutive assessments are made, following the procedure in the SOM. 
At least the last readings must be within the ranges provided above in order for the subject 
to qualify.
9. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
SWD patients fulfilling any of the following criteria are not eligible for inclusion in this 
study:
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations.
2. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes.
3. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
subjects participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
4. Current use of a pacemaker.
5. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.
6. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, at 
Screening or each Baseline, if this ideation occurred in the past 6 months, or “yes” on any 
item of the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious 
Behavior” (item also included in the Suicidal Behavior section), if this behavior occurred 
in the past 2 years.
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8. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception from 
start of taking the study medication in the first period until stopping the medication in the 
second treatment period and for 3 additional days after AND an additional barrier method 
of contraception will be used while taking the study medication and for 3 additional days 
in both treatment periods.  
Highly effective contraception methods include:

Female sterilization (have had surgical bilateral oophorectomy (with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 m prior to screening). The vasectomized male partner 
should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement 
of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception 
In case of use of oral hormonal contraception or other forms of hormonal contraception 
(e.g. vaginal ring or transdermal patch) women should have been stabile on the same 
pill/method for a minimum of 3 months before starting study treatment. In case of use of 
an IUD or IUS, the device or system should have been placed and well tolerated by the 
patient for a minimum of 3 months before starting the study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential
9. Sexually active males unwilling to use a condom during intercourse while taking 
investigational drug and for 3 days after stopping investigational drug in both study 
periods. A condom is required for all sexually active male participants to prevent them 
from fathering a child AND to prevent delivery of the investigational drug via seminal 
fluid to their partner.
10. Heavy smokers who smoke more than 10 cigarettes a day and occasional or light smokers 
(not more than 10 cigarettes per day) who are not willing to, or in their own or the
investigators opinion are not able to refrain from tobacco/nicotine use for at least 12 hours 
without nicotine craving or other withdrawal symptoms (e.g. anxiety, irritability, 
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11. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in 
case of participation in the study. The Investigator should make this determination in 
consideration of the subject’s medical history and/or clinical or laboratory evidence of any 
of the following:

History (past 5 years) of inflammatory bowel disease, peptic ulcers, gastrointestinal 
including rectal bleeding with the exception of bleeding from otherwise asymptomatic 
hemorrhoids;

Any history of major gastrointestinal tract surgery such as gastrectomy, 
gastroenterostomy, or bowel resection;

History (past 5 years) of pancreatic injury or pancreatitis;

Liver disease or liver injury as indicated by abnormal liver function tests as specified 
below. ALT (SGPT), AST (SGOT), γ-GT, alkaline phosphatase, and serum bilirubin 
will be tested.  

Serum bilirubin must not exceed 1.2 x ULN

γ-GT, ALT, AST, and alkaline phosphatase must not exceed 1.5 x ULN

History or presence of impaired renal function as indicated by clinically significantly 
abnormal creatinine or BUN and/or urea values, or abnormal urinary constituents 
(e.g. albuminuria).

Evidence of urinary obstruction or difficulty in voiding at Screening.
12. History of hematological diseases in the past 5 years.
13. Abnormalities on hematology lab tests at Screening or either Baselines that are considered 
clinically relevant by the Investigator.
14. History of immunodeficiency diseases, including a positive HIV (ELISA and Western 
blot) test result.
15. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, 
excludes a subject. Subjects with a positive HCV antibody test should have HCV RNA 
levels measured. Subjects with positive (detectable) HCV RNA should be excluded.
16. Any clinically significant infectious disease which has not resolved within 2 weeks prior 
to dosing.
17. Vaccination with any live, attenuated vaccine in the 3 months prior to dosing.
18. History of unstable thyroid disease in the past 5 years or any clinically relevant 
abnormality on plasma thyroid stimulating hormone test (TSH) at Screening. Thyroid 
disease that is stable and well-controlled with hormone supplementation but without
antithyroid medication is acceptable if TSH is normal at Screening and hormone 
supplementation dose has been stable for at least 12 months prior to Screening.
19. History of drug abuse or unhealthy alcohol use# within the 12 months prior to dosing, or 
evidence of such abuse as indicated by the laboratory assays conducted during Screening 
or each Baseline.
#Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined as 
“Five or more drinks on the same occasion on each of 5 or more days in the past 30 days."


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20. History of recreational cannabis use within four weeks prior to dosing, or evidence of such 
use as indicated by the laboratory assays conducted during Screening or each Baseline. 
This exclusion criterion applies even if cannabis use is legalized where the site is located. 
Any prescribed, medicinal use of cannabis is to be handled according to the prescription 
drug usage criteria defined below.
21. Use of any medication specified in the prohibited medication section.
22. Subjects, for whom it is not safe to discontinue or who are unwilling to discontinue use of 
modafinil, hypnotics, and antihistamines for the periods specified in the prohibited 
medication section.
23. Heavy caffeine consumers, i.e. subjects who consume greater than 850 mg of caffeine per 
day (approximate equivalent of three tall cups of Starbucks coffee) in coffee, tea, or other 
caffeine-containing drinks. 
24. History of any neurological or psychiatric disorders in the past 5 years, with the exception 
of a short duration depressive episode, if it has completely resolved at least 12 months 
before Screening.
25. History of epilepsy or of seizures or convulsions of any kind in the past 5 years.
26. History of head trauma leading to clinically significant symptoms in the past 5 years.
27. Any history of any chronic eye disease affecting the retina.
28. Any history of surgery on the retina, including laser treatment, or plans for such surgery 
during the study.
29. Subjects who have high risk of obstructive sleep apnea, indicated by score of 5 or more on 
the STOP-BANG questionnaire.
30. Presence of any sleep disorder other than SWD, as confirmed by PSG at Screening.
Specifically, the subjects must present with apnea-hypopnea index (AHI) <15 and periodic 
leg movement in sleep with arousal index (PLMSArI) < 15.
31. Any general medical condition that could account for excessive sleepiness during night 
shifts.
32. Considered by the investigator to be unlikely to comply with the study protocol
33. At screening or each baseline, presence of any such medical condition or abnormalities on 
safety examinations that are not mentioned among the exclusion criteria above, but 
indicate significant risk of safety for subjects participating in the study.
Repeat Laboratory assessments: In the case where a safety laboratory assessment at 
Screening or either Baseline is outside of the range specified above, the assessment may be 
repeated once prior to randomization/treatment. If the repeat value remains outside of the 
specified ranges, the subject is excluded from the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be willing to use a highly effective contraception from 
start of taking the study treatment in the first treatment period to completing the study 
treatment in the second treatment period and for 3 additional days after AND also willing to 
use an additional barrier method of contraception while taking the study medication and for 
3 additional days after in both treatment periods. Highly effective contraception methods are
one of the following: 

Female sterilization (have had surgical bilateral ophorectomy (with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 m prior to screening). The vasectomized male partner 
should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral hormonal contraception or other forms of hormonal contraception 
(e.g. vaginal ring or transdermal patch) women should have been stabile on the same 
pill/method for a minimum of 3 months before starting study treatment. In case of use of an 
IUD or IUS, the device or system should have been placed and well tolerated by the patient 
for a minimum of 3 months before starting the study treatment.
Barrier contraception methods include: male condom, female condom, diaphragm or cervical 
cap. Spermicide must be used with diaphragm and cervical cap.
Women of child bearing potential are defined as all women physiologically capable of 
becoming pregnant. Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential.


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Sexually active males should be reminded of the requirement to wear a condom for 3 days 
after the last administration of investigational drug for the following reasons:

Prevent pregnancy in a female partner
AND

Prevent  delivery of investigational drug via seminal fluid to their partner as study 
treatment may involve unknown risks to the fetus if pregnancy were to occur
If there is any question that the subject will not reliably comply, the subject should not be 
entered or continue in the study. Male subjects should be informed that if a female partner 
becomes pregnant while he is enrolled in the study, contact with the female partner will be 
attempted to request her consent to collect pregnancy outcome information. Please refer to 
Section 4.2 (Exclusion criteria) for details of contraception requirements for the study.
5.2
Prohibited treatment
Use of the treatments displayed in Table 5-1 is NOT allowed after the indicated period.
Table 5-1
Prohibited medication
Medication
Prohibited period
Action to be taken
Drugs that are known to strongly inhibit or 
induce the metabolizing enzymes 
CYP3A4/5, as they may alter the PK of 
LML134. 
From at least 5 half-lives 
before first dosing 
through end of study
Do 
not 
enroll 
subject 
or 
initiate 
treatment. Discontinue study treatment 
during treatment periods.
Drugs or other non-pharmacological 
interventions that might affect circadian 
rhythm (e.g. melatonin, light therapy).
From start of screening 
through end of study.
Do 
not 
enroll 
subject 
or 
initiate 
treatment. Discontinue study treatment 
during treatment periods.
Modafinil and hypnotics
From at least 5-times the 
half-life of the drug prior 
to the start of screening 
through end of study.
Do 
not 
enroll 
subject 
or 
initiate 
treatment, 
unless 
it 
is 
safe 
to 
discontinue modafinil and hypnotics 
and the subject agrees to discontinue 
use of modafinil and hypnotics. Should 
the need arise for a subject to take 
modafinil or hypnotics during the study, 
the study drug should be discontinued.
All CNS-active medication including OTC 
cough suppressant (except modafinil and 
hypnotics)
From start of screening 
through end of study.
Do 
not 
enroll 
subject 
or 
initiate 
treatment. Should the need arise for a 
subject to take CNS active medication
during the study, the study drug should 
be discontinued.
Antihistamines, in particular, first 
generation (i.e. brain penetrant, sedative)
antihistamines (chlorpheniramine, 
diphenhydramine, promethazine, and 
hydroxyzine)
From at least 5-times the 
half-life of the drug prior 
to the start of screening 
through end of study.
Do 
not 
enroll 
subject 
or 
initiate 
treatment, 
unless 
it 
is 
safe 
to 
discontinue antihistamines and the 
subject agrees to discontinue use of 
antihistamines. Should the need arise 
for a subject to take antihistamines
during the study, the study drug should 
be discontinued.


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Medication
Prohibited period
Action to be taken
Any other drug, herbal or food supplement 
that might induce sleepiness/somnolence 
or sedation as a known and common AE 
(>1%) according to the label of the drug
and medical history of the subject indicates 
that the excessive sleepiness might be 
related to use of these drugs or food 
supplements. Examples include 
antiemetics, alpha-adrenergic blocking 
agents, some beta adrenergic blocking 
agents, muscle relaxants and other drugs.
From start of screening 
through end of study.
Do 
not 
enroll 
subject 
or 
initiate 
treatment. Should the need arise for a 
subject to take such medication during 
the study, the study drug should be 
discontinued.
Combination drug treatments that contain 
caffeine.
From at least 12 hours 
before dosing to end of 
assessments during the 
treatment period
Discontinue 
study 
treatment 
and 
remove subject from efficacy analysis.
5.3
Dietary restrictions and smoking

No alcohol for 12 hours before each dosing. Consumption of alcohol is not permitted at 
any time while the subjects are domiciled. During the out-patient phase of the study 
consumption of alcohol will be restricted to no more than one drink per day for women 
and no more than two drinks per day for men. A standard drink (in the United States) is 
equal to 14.0 grams (0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is 
found in

12 fluid ounces of regular beer (5% alcohol content)

5 fluid ounces of wine (12% alcohol content)

1.5 fluid ounces or a “shot” of 80-proof (40% alcohol content) distilled spirits or 
liquor (e.g., gin, rum, vodka, whiskey)

No cannabis use for 4 weeks before first dosing until after Study Completion evaluation.

Smokers should not smoke more than 10 cigarettes per day during the entire study period. 
Consumption of nicotine containing products is also restricted to equivalent amount
(corresponding to 10 cigarettes) during the entire study period. Smoking is completely
prohibited during the treatment period each night from about 2 hours before dosing until 
completion of all efficacy assessments.

Intake of methlyxanthine (e.g. caffeine, theophylline, theobromine) containing food or 
beverages must be discontinued 12 hours before dosing. Consumption of such foods and 
beverages (i.e., coffee, tea, soda, chocolate) is not permitted at any time while the subjects 
are domiciled. During the out-patient phase of the study caffeine consumption will be 
restricted to no more than 850 mg of caffeine per day.

No grapefruit or grapefruit juice is to be consumed for 14 days prior to dosing until 7 days 
following the last dose.
Subjects should take medication when administered by site staff. Study medication should be 
administered with a glass of water. Subjects should not chew the medication, but swallow it 
whole.
Meals and snacks will be served at appropriate times according to the subjects' sleep/wake 
schedules and so as not to interfere with the Assessment schedule. Subjects will follow a 
standard weight maintaining diet while domiciled.


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5.4
Other restrictions
Not applicable.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drug(s)
Table 6-1
Overview of study medication
Study drug 
name
Formulation
Appearance
Unit dose
Packaging
Provided 
by
LML134
Capsule
 
 
 
Open label 
bulk
Novartis
Placebo
Capsule
 
 
Open label 
bulk
Novartis
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
6.2
Treatment arms
Study treatments are defined as:
!
A:  single dose of 
 LML134, on each of two consecutive nights
!
B:  single dose of placebo to 
 LML134, on each of two consecutive nights
Subjects will be randomized to one of the following 2 treatment sequences in the ratio of 1:1.
Table 6-2
Definition of treatment sequences
Sequence
Period 1
Period 2
1
A
B
2
B
A
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6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual subjects by way of a randomization 
number, which will be in the range of 5101-5146.
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive.  The Subject number assigned to a subject at Screening remains the 
unique identifier for the subject throughout the study. For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
Replacement randomization numbers will be in the range of 6101-6146. If a subject requires a 
replacement, the replacement subject will be assigned a randomization number corresponding 
to the original subject (e.g. Subject 6103 would replace Subject 5103). Any additional 
subjects enrolled will use sequential subject numbering.
Table 6-3 details the general details of the numbering of the subjects once randomized to 
treatment.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio. The randomization scheme for subjects 
will be reviewed and approved by a member of the Randomization Office.
Subjects will be randomized within the electronic NIRT system. Follow the details outlined in 
the Site Operations Manual regarding the process and timing of treatment assignment and 
randomization of subjects.
Table 6-3
Treatment Assignment Numbering
Cohort
Randomization numbers
Replacement randomization numbers
I (n = 46)
5101 - 5146
6101 - 6146
6.4
Treatment blinding
This is a subject- and investigator-blinded study. Subjects and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).


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Drug product will be supplied in bulk, so an unblinded pharmacist who is independent of the 
study team will be required in order to maintain the blind. This unblinded pharmacist will 
receive a randomization list or treatment allocation cards from Drug Supply Management with 
the appropriate treatment allocation numbers. Appropriate measures must be taken by the 
unblinded pharmacist to ensure that the treatment assignments are concealed from the rest of 
the site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study:

Unblinded field monitor(s)

Unblinded sample analyst(s) (PK)
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be 
unblinded through review of source documentation compiled by the unblinded pharmacist, 
which details treatment allocation to individual subjects. The unblinded monitors will also be 
able to review the treatment allocation cards/randomization list provided to the unblinded 
pharmacist. The names of the unblinded monitor(s) are detailed in the Monitoring Plan.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-4. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker 
expert) are allowed to access treatment assignment information for the purpose of conducting 
interim analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.


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Table 6-4
Blinding and unblinding plan
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim Analysis 
& dose 
escalation
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff (see text 
for details) 
B
UI
UI
UI
Drug Supply and 
Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff (see 
text for details)
B
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
Independent committees used 
for assessing interim results
NA
NA
NA
NA
All other sponsor staff not 
identified above
B
B
UI
UG
B Remains blinded
NA Not applicable
UI Allowed to be unblinded on individual patient level
UG Allowed to be unblinded on treatment group level
6.5
Treating the subject
LML134 will be administered to the subject orally at the study site once a day in the evening. 
LML134 and Placebo will be provided as 
 capsules. 
 
See the Site Operations Manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted.
6.7
Emergency breaking of assigned treatment code
Emergency unblinding must only be undertaken when it is essential to treat the subject safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. 
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Emergency treatment code breaks are performed using the NIRT system. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide 
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The investigator will then receive details of the investigational drug 
treatment for the specified subject and a fax or email confirming this information. 
The investigator must also immediately inform the study monitor that the code has been 
broken.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with LML134, as detailed in Section 8.7.
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
6.9
Recommended treatment of adverse events
There is no specific antidote to LML134. Any adverse events should be managed 
symptomatically according to standard of care and applicable clinical guidelines.
In case of insomnia, non-pharmacological treatments should be attempted first.
6.10
Rescue medication
Not applicable.
6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes or any change in dose of known medication after the subject was enrolled into the 
study and until the study completion.
All medications, vaccinations, over-the-counter drugs and significant non-drug therapies 
(including physical therapy, light therapy and blood transfusions) administered or taken 
within the timeframe defined in the entry criteria and prohibited medication sections until 
Study Completion, must be reported in the CRF on the Concomitant medications/Significant 
non-drug therapies page after the start of the study.
Medication entries should be specific to trade name, the route of administration, the start and 
discontinuation date, and the reason for therapy.


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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation 
in the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 9.2 and the Site Operations Manual.  Documentation of attempts to contact the subject 
should be recorded in the source documentation.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator.
Study treatment must be discontinued under the following circumstances:

Subject decision - subjects may choose to discontinue study treatment for any reason at 
any time.

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the subject’s safety or loss of 
significant data.

Any occurrence of protocol exclusion criteria #6, #13, #19, #20, at the second Baseline 
visit.

Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting))

Use of prohibited treatment as described in the relevant section

Emergence of the following adverse events: 

An SAE (including seizure) that is suspected to be related to study drug

An AE which is severe and suspected to be related to study drug

Infection of clinical concern, independent of the nature of the infection

Hyperthyroidism, evidenced by symptoms consistent with the clinical manifestation 
of the disease and confirmed by lab results of thyroid hormone levels


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
Any impairment or blurring of vision or other visual complaints that might suggest 
retinal damage (e.g. curtain like shadow in the visual field, seeing sparks or flashes of 
light, appearance of many floaters, etc)

Any significant change in behavior of the subject (e.g. signs of confusion, agitation or 
other symptoms indicating emerging psychiatric problems)

Liver events, as defined in Table 15-2-Appendix 1 of the protocol

Renal events, as defined in Table 16-1 Appendix 2 of the protocol

Any of the following laboratory abnormalities: 

Total white blood cell count <2000 cells/mm; <2.0 x 10e9 /L

Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L

Any other laboratory abnormalities that in the judgment of the investigator, taking 
into consideration the subject’s overall status, prevents the subject from continuing 
participation in the study.

The following deviations from the prescribed dose regimen for the study drug

One or more missed doses

Dose of study drug was different from that specified in the study protocol
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason 
for the subject’s premature discontinuation of study treatment.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3, Withdrawal of informed consent). Where possible EOS 
assessments should be completed before they leave the sleep laboratory and they should be 
requested to return within 7 to 14 days to complete the follow-up visit. If they fail to return for 
future visits for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the subject/pre-designated contact as specified in Section 7.4. (Lost to follow-up). 
This contact should preferably be done according to the study visit schedule,
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events


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7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable attempt (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her consent 
and record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.


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7.5
Study Stopping rules
The study will be stopped, and no further dosing decisions will be taken pending a full safety 
review, if any of the following criteria are met:

1 or more study-drug related SAEs (including seizure) are reported

1 or more subjects in the study experience study-drug related newly emerging symptoms 
indicating retinal damage, if the retinal damage is confirmed by appropriate ocular 
examinations

2 or more subjects in the study experience any of the following: 

Total white blood cell count below 2000 cells/mm; 2.0 x 10e9/L

Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L

4 or more subjects in the study experience any of the following: 

Symptoms of hyperthyroidism with elevated thyroid hormone levels in blood

A similar AE which is assessed as either moderate or severe in intensity, and is 
potentially related to study-drug

The Principal Investigator (or his/her designee) and the Sponsor consider that the number 
and/or severity of adverse events justify discontinuation of the study

General Note: In the case where a safety laboratory assessment are outside of the range 
specified above, the assessment may be repeated once. If the repeat value remains outside 
of the specified ranges, the stopping rule is met.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
subjects must be seen as soon as possible and treated as a prematurely discontinued subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection
of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.














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X Assessment to be recorded in the clinical database
1 Visit structure given for internal programming purpose only
2 Abbreviated neurological exam only.
3 Sleep diary should be completed during baseline for 3 days prior to dosing, in conjunction with the patients 3 awake nights even if 1 awake night is spent at the sleep lab
4 Sleep diary to be completed when subject wakes up from sleep.
5 Source only.
6 Serum Pregnancy test. Fertility assessment required at screening only.
7 Urine pregnancy test acceptable
8 Results of the baseline assessments (including safety labs and drug screen) must be available before dosing. 
12 Completion for this Treatment Period.
13 Screening assessments will occur over multiple days.  The daytime sleep PSG and nighttime MSLT will be performed in the sleep lab on consecutive days that follow at 
least 3 consecutive nights following a shift work schedule. 
14 If a subject spends an additional supervised night in the sleep lab to complete their third consecutive awake night this must be documented in the sites source records. 
Records should include the date of the stay and the schedule they followed during their stay.
15 EOS/ET assessments should not be repeated if performed during the follow-up visit at the end of the Treatment Period. If subjects terminate early the EOS 
assessments should be completed prior to the patient leaving the sleep laboratory and the patient should return for the follow-up visit. 
16 The Follow-up visit in Treatment Period 1 can also serve as the Baseline 2 visit if Treatment Period 2 Day 1 will begin within 7 days after the visit
17 Follow-up assessments should be completed for any patient who receives test drug 7 to 14 days after they discontinue study treatment in each treatment period.
18 Safety follow-up phone call to be performed 30 days after last visit for enrolled subjects.
19 Up to 5 weeks wash out is allowed between the last dose in Treatment period 1 and the first dose of period 2 to allow for scheduling flexibility. Timing of the second 
baseline visits should be adjusted accordingly.
20 The assessments should be performed as close as possible to the dosing time. If timing of the daytime sleep period would not allow completion of all necessary 
assessments before dosing, the physical and neurological exams, CSSR-S and alcohol/drug/cotinine screen can be completed before the subject goes to sleep in the 
22 Dosing should be performed at approximately 22:00.
23 9.5h assessments are detailed in the details for night time assessments table
24 Safety assessments may commence after completion of efficacy assessments.
25 Safety assessments should be done prior to discharge. These assessments can be completed after the efficacy assessments 
 are completed, 
if the patients decide to leave the site in the morning. If the subject stays in the clinic to sleep these assessments can be done after the recovery sleep is completed
26 Any occurrence of protocol exclusion criteria #6, #13, #19, #20, at the second Baseline visit would result in discontinuation
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Details for night time (highly repetitive) assessments
Epoch
Visit Name
Visit Numbers
Days
Time (post-first dose)
Dosing
MSLT
Screening
Screening
11
-42 to -8
-
X
Baseline 1
101
-7 to -1
-
Treatment Period 1
Day 1
102
1
-2h
0h
X
Day 2
103
2
2.5h
3.5h
X
4.5h
5.5h
X
6.5h
7.5h
X
8.5h
9.5h
X
22h
24h
X
Day 3
104
3
26.5h
27.5h
X
28.5h
29.5h
X
30.5h
31.5h
X
32.5h
33.5h
X
Baseline 2
201
17 to 24
-
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Epoch
Visit Name
Visit Numbers
Days
Time (post-first dose)
Dosing
MSLT
Treatment Period 2
Day 1
202
25
-2h
0h
X
Day 2
203
26
2.5h
3.5h
X
4.5h
5.5h
X
6.5h
7.5h
X
8.5h
9.5h
X
22h
24h
X
Day 3
204
27
26.5h
27.5h
X
28.5h
29.5h
X
30.5h
31.5h
X
32.5h
33.5h
X
X Assessment to be recorded in the clinical database
1 Screening assessments will occur over multiple days.  The daytime sleep PSG and nighttime MSLT will be performed in the sleep lab on consecutive days that follow at 
least 3 consecutive night following a shift work schedule. 
2 This time point for practice only. Data will not be collected.
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject’s representative gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible 
given his/her understanding. If the subject is capable of doing so, he/she must indicate assent 
by personally signing and dating the written informed consent document or a separate assent 
form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
The procedures set out in the main consent form concerning the storage, maintenance of 
privacy, and release of the data or specimens for the main study will also be adhered to for 
any future research. Any changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included 
in this study.
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8.3
Subject screening
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis.
The initial screening period will include a daytime visit where eligibility will be assessed. 
This will be followed by at least two weeks (14 days) when the patient continues with their 
usual work schedule and will fill out a paper sleep diary (outpatient). The patient will come 
into the sleep lab to complete the inpatient daytime sleep PSG and nighttime MSLT on the 
day that directly follows at least 3 consecutive nights awake conforming to that subject’s night
shift schedule.
Information on what data should be collected for screening failures is outlined in the 
Site Operations Manual.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Hepatitis and HIV Screen
All subjects will be screened for HIV, Hepatitis B and C. See the Site Operations Manual for 
details.
8.4.2
Alcohol Test, Drug Screen, and Cotinine Test
All subjects will be screened for substances of abuse and cotinine. See the Site Operations 
Manual for details, including what information must be captured in the source documentation 
and CRF for smokers.
8.4.3
STOP-BANG questionnaire
The STOP-BANG questionnaire was designed to screen for symptoms of obstructive sleep 
apnea (OSA) in surgical patients Chung et al 2008, but was validated in broader population 
referred to a sleep laboratory for overnight PSG Boynton et al 2013. Subjects will complete 
the questionnaire during screening to assess eligibility prior to the subject completing the 
14 days of sleep diary. See the SOM for details.


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8.5
Efficacy / Pharmacodynamics
8.5.1
MSLT
The MSLT is a validated objective measure of the ability or tendency to fall asleep. It is 
intended to measure physiological sleep tendency in the absence of alerting factors. 
The MSLT is based on the assumption that physiological sleepiness decreases sleep latency. 
That is, the tendency to fall asleep should increase as physiological sleepiness increases. 
MSLT is sensitive to both trait and state level of CNS arousal (Littner et al 2005;
Arand et al 2005).
MSLT will be used during screening to confirm moderate to severe sleepiness during night 
shift in SWD patients. It will also be performed after study drug administration to measure 
LML134 effect on wakefulness.
Screening MSLT will be performed locally at each site by a sleep technologist experienced in 
the procedure using the same approach as implemented for the efficacy MSLT. The screening 
MSLT results will be reviewed and scored locally by an experienced sleep expert (such as a 
sleep medicine specialist). 
Post dose MSLT will be performed at time points specified in the Assessment schedule
locally at each site by a sleep technologist experienced in the procedure. The results will be 
scored by a central reader.
The parameters measured and recorded will be the same for the efficacy (post dose) and the 
screening MSLT, i.e. start and end times of each nap or nap opportunity, latency from lights 
out to the first epoch of sleep for each nap, and number of sleep-onset REM periods.
See the SOM for details.
8.5.2
Clinical Outcome Assessments (COAs)
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8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed.
8.6.1
Physical Examination
See Site Operations Manual for details. 
8.6.2
Vital signs
!
Body temperature
!
Blood pressure (BP)
!
Pulse 
8.6.3
Height and weight
!
Height
!
Body weight
!
Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2)
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8.6.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should be contacted.
8.6.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, reticulocyte count, white blood cell count with 
differentials (e.g. neutrophils, basophils, eosinophils, monocytes, lymphocytes presented as % 
of total white blood cell count and as absolute concentrations), and platelet count will be 
measured. Coagulation testing including prothrombin time (PT) also reported as INR and 
activated partial thromboplastin time (aPTT) will be measured.
8.6.4.2
Clinical Chemistry
Sodium, potassium, calcium, magnesium, chloride, creatinine, BUN/urea, uric acid,  albumin, 
CRP, alkaline phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, 
amylase, lipase, CK, glucose, total cholesterol, triglycerides, thyroid stimulating hormone 
(TSH).
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
8.6.4.3
Urinalysis
Dipstick measurements for protein, blood, and WBC/leukocytes will be performed. If the 
dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be sent 
for microscopic analysis of WBC, RBC and casts, furthermore the protein-creatinine ratio 
(PCR) and the albumin-creatinine ratio (ACR) will also be measured.
8.6.5
ECG evaluation
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTc
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the 
ECG machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) 
(as applicable) to assess eligibility. See the Site Operations Manual for additional details.
Clinically significant abnormalities must be reported in the AE CRF.


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8.6.6
Pregnancy and assessments of fertility
Pregnancy Testing
Pregnancy tests are required of all female subjects regardless of age or reported sterilization. 
The result of this test must be received before any female subject may be dosed. See the 
Assessment schedule (Section 8.1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements. A positive urine 
pregnancy test requires that study treatment cannot be initiated in either period or has to be 
immediately interrupted until serum β-hCG is performed and found to be negative.
Refer to Section 9.6 for details on Reporting Pregnancy.
Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at Screening/Baseline.
8.6.7
Polysomnography
PSG is the gold standard method to evaluate sleep. In the present study, PSG will be 
performed at Screening to exclude any other sleep disorder than SWD. Screening PSG will be 
scored locally at each site by personnel experienced in the procedure (such as sleep 
technologist and sleep specialist). PSG will also be performed during the daytime sleep 
following the first dose of LML134 in each treatment period to assess any effect of LML134 
on sleep. Post dose PSG will be scored centrally.
Technical details of PSG are specified in the SOM.
8.6.8
Neurological Examination
Neurological 
assessments 
will 
be 
performed 
at 
time 
points specified 
in 
the 
Assessment schedule to investigate the potential effect of the study drug on gait, coordination, 
tremor, muscle tone and biceps reflexes. Pre and post dose assessments should be conducted 
by the same study physician wherever possible. 
Details of the examination and scoring of the responses are specified in the SOM.


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8.7
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule 
(Section 8.1). Follow instructions outlined in the Site Operations Manual regarding sample 
collection, numbering, processing and shipment. See Section 8.9 regarding the potential use of 
residual samples.
PK samples will be obtained and evaluated in all subjects, except the samples collected during 
treatment with placebo.
LML134 will be determined in plasma by a validated LC-MS/MS method; the anticipated 
Lower Limit of Quantification (LLOQ) is 0.02 ng/mL. Concentrations will be expressed in 
mass per volume units and will refer to the free base.
Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled 
as such in the Bioanalytical Data Report. Concentrations below the LLOQ will be treated as 
zero in summary statistics for concentration data only. They will not be considered for 
calculation of PK Parameters (with the exception of the pre-dose samples).
The PK blood collection log and sample labeling and shipment instructions are provided in 
the Site Operations Manual.
Conventional PK parameters will not be calculated due to the limited sampling schedule. 
However, plasma concentrations will be listed and summary statistics for concentrations will 
be provided for plasma. The data will be part of the over-all Population PK model.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
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The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively.
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. The severity grade 
mild: 
usually transient in nature and generally not interfering with normal activities
moderate: sufficiently discomforting to interfere with normal activities
severe: 
prevents normal activities
2. its relationship to the study treatment 

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness 
criteria have been met  
5. Action taken regarding investigational treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).


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Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications.  Once an adverse event is detected, it must be followed 
until its resolution or until it is judged to be permanent, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
AEs will be collected in the CRF for subjects that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH-E2D Guideline 2003).


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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to ICH-E2D Guideline 2003).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section 9.2.2.
9.2.2
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis.
Randomized Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last administration of study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence as described below.
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Chief Medical Office 
and Patient Safety (CMO & PS) Department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN) to inform all investigators involved in any study with the 
same study treatment that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.   Note:  SAEs must be reported to 
Novartis within 24 hours of the investigator learning of its occurrence/receiving follow-up 
information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with 
the results provided via the standard electronic transfer.  If results will not be available from 
the central laboratory within 24 hours, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include


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
Repeating liver chemistry tests two or three times weekly. Testing should include ALT, 
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation into 
direct and indirect bilirubin is required. To rule out muscular origin of transaminase 
elevations, CPK should be measured along with liver chemistry tests. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study drug 
has been discontinued and the subject is asymptomatic. Retesting should be continued up 
to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details. 
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the Dosing Log CRF. Study treatment errors are only to be reported to Chief 
Medical Office and Patient Safety (CMO& PS) department if the treatment error is associated 
with an SAE.


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All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety 
(CMO& PS). As such, instances of misuse or abuse are also to be reported using the SAE 
form/CRF. Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dosing 
Log CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
Women who are considered to be of child-bearing potential, are required to use highly 
effective contraception and an additional barrier method, if they are enrolled in this study, 
thus pregnancy is not an expected outcome for any female study participant. However, in the 
case that a pregnancy in a female study participant should occur, please follow the below 
reporting guidelines.
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the subject may stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The subject may continue all other protocol assessments.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.


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9.7
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior. The C-SSRS must be administered at each 
visit, including unscheduled visits.
The C-SSRS, which uses a semi-structured interview to probe subject responses, will be 
administered by an individual who has received training and certification in its administration. 
At the first study visit, the “baseline/screening” version of the C-SSRS will be administered. 
This version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime 
and during a predefined period. At subsequent visits, the “since last visit” version will be 
administered.
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the C-SSRS or “yes” on any item of the Suicidal Behavior section, 
the subject must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the investigator in consultation with the mental health professional to whom the subject is 
referred.
In addition, all life-threatening events must be reported as SAEs. For example, if a subject 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be 
reported if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the Suicidal Behavior section) should be reported as AEs and 
assigned the appropriate severity grade.
All SAEs relating to suicidal behavior must be reviewed by the Safety Management Team or 
Early Project Teams.
9.8
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the
Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.


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10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The monitor will visit the site to check the completeness of subject records, the accuracy of 
data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and ensure that study drug is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the monitor 
during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be 
used for all primary and safety variables. Additional checks of the consistency of the source 
data with the CRFs are performed according to the study-specific monitoring plan. 
No information in source documents about the identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Novartis. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive copies of the subject data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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10.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff or CRO working on behalf of Novartis who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
The post dose PSG and MSLT data will be analyzed by a central reading vendor and provided 
to Novartis via electronic data transfer.
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
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11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The full analysis set will include all subjects that received any study drug and had any 
post-baseline assessment.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
All available data under safety analysis set will be used for reporting purpose.
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment 
sequence and subject.
All available data under safety analysis set will be used for reporting purpose.
11.4
Analysis of the primary variable(s)
The mean of multiple sleep latency scores is the primary variable of this study.
11.4.1
Primary Variable(s)
Each subject will undergo a sleep latency test assessment at each period, at approximately 
1:30, 3:30, 5:30 and 7:30 in Day 2 (Night 1) and Day 3 (Night 2) (Days 12 and 13 in 
Treatment Period 2). The mean value of all the sleep latencies from a subject within a period 
will be defined as mean sleep latency score for that subject for that period.
11.4.2
Statistical model, hypothesis, and method of analysis
Nicotine is a powerful substance to stimulate wakefulness and attention. At same time 
screening MSLT reflects the stage of severity of shift work disorder patients. Therefore both 
smoking status (/nicotine intake) and MSLT at screening will be considered as covariates in 
the model.


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For statistical analysis purposes; subjects under full analysis set with all available MSLT 
information from both the periods will be included in the analysis.
Mean sleep latency score data will be analyzed using a mixed effect ANOVA model with 
treatment smoking status at screening, screening MSLT, treatment interaction with screening 
MSLT and smoking status and period as fixed effects and subject as a random effect. Least 
square estimates for each treatment and treatment difference (LML134 vs placebo) along with 
95% confidence interval will be reported. In studies with short treatment duration in SWD 
patients or healthy shift workers the usual approach is to compare post-dose conditions and 
not change from baseline. The reason for this approach is the high variability in MSLT 
(average of at least three tests is needed as baseline) and that baseline and post-dose MSLT 
results need to be time matched, as MSLT results depend on circadian rhythm.
The following assessments will be performed to judge efficacy of LML134:
a. Statistical significance: One sided (superiority) p-value of LML134 vs placebo from above 
fitted ANOVA model will be reported.
A p-value <0.1 will be considered as a positive sign for statistical significance.
b. Estimate of treatment difference (LML134 vs Placebo) will be reported.
An estimate of treatment difference > 1 minute would be considered as significant.
In addition from the above model, effect of LML over placebo in each subgroup (smoking 
status and MSLT (<6 and >=6)) will be estimated through 95% CI of interaction effects.
Same analysis will be performed at interim.
Graphical display:
Subjects under safety analysis set will be used for reporting. For a thorough investigation of 
sleep latency time profiles, data from LML134 and placebo will be superimposed using 
suitable graphical tools like boxplot or arithmetic mean (SD) statistics.
Descriptive summary:
Subjects under safety analysis set will be used for reporting. Sleep latency data will be 
summarized by treatment and time point. Summary statistics like N, mean, SD, CV, and range 
will be reported.
11.4.3
Handling of missing values/censoring/discontinuations
If a subject has missing data at any timepoint during night 1 the corresponding timepoint from 
night 2 will be used to impute the value and vice versa. If a subject has a timepoint missing 
for both night 1 and 2 then MSLT will be calculated over all the available time points.


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11.4.4
Sensitivity analyses
Mean of multiple sleep latency score is essentially a positive outcome. Thus a supportive 
analysis will be performed using log transformed mean sleep latency scores. Log transformed 
mean sleep latency score data will be analyzed using a mixed effect ANOVA model with 
treatment and period as fixed effects and subject as a random effect. Least square estimates 
for each treatment and treatment difference (LML134 vs placebo) along with 95% confidence 
interval will be back transformed to report in original scale.
11.4.5
Supportive analysis
The analysis explained in Section 11.4.2 will be performed in a Bayesian platform with non-
informative priors for treatment effects. The probability of treatment difference more than 0 
and 1 will be reported to assess the similarity with primary analysis.
Futility Analysis:
The same analysis will be performed during interim analysis. The predictive distribution of 
treatment effect given the available data at interim will be evaluated to assess the chance of 
meeting proof of concept criteria at the end of complete trial. Explicit decision criteria for 
interim will be discussed in statistical analysis plan.
11.5
Analysis of secondary variable(s)
Overall 
safety 
profile 
is 
assessed 
by 
AEs, 
laboratory 
data, 
and 
ECG.
Additionally, pharmacokinetics and MSLT scores are assessed under safety.
11.5.1
Efficacy / Pharmacodynamics
Subjects with all available MSLT assessments from both the periods under full analysis set 
will be used for reporting.
Here we want to take a look at sleep latency more vividly; i.e. rather than looking at overall 
score we need to look at the score of each time point separately.
Each subject will undergo a sleep latency test assessment at each period, at approximately 
1:30, 3:30, 5:30, and 7:30 in Day 2 (Night 1) and Day 3 (Night 2) (Days 12 and 13 in 
Treatment Period 2). The mean value of sleep latencies averaged over two consecutive nights 
for each time point for each subject in each period will be defined as sleep latency score for 
that time point for that subject.
An arithmetic mean +/- SD time profile (time-points: 1:30 AM, 3:30 AM, 5:30 AM, and 
7:30 AM) plot will be provided for each treatment. A summary table will be created to report 
n (number of evaluable subjects), mean, SD, and range for each treatment at each time point.
A mixed model repeated measure analysis of variance will be performed over mean sleep 
latency scores with treatment, period, time, and treatment*time as fixed effects; correlated 
observations coming from the same subjects will be adjusted using a subject level random 
effect and suitable covariance structure. The overall treatment effect for LML134 vs placebo 
will be reported along with a 95% CI.


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11.5.2
Safety
All analysis will be performed under safety analysis set.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged.
Summary statistics of height, weight, temperature, blood pressure, and pulse rate will be 
provided by treatment and visit/time using statistics like N, mean, median, standard deviation, 
and range.
The same data will be plotted using arithmetic mean-SD graphs over time for each parameter 
separately. Separate lines will be drawn for each treatment in order to see any potential 
differences.
ECG evaluations
All ECG data will be listed by treatment group, subject, and visit/time, and abnormalities will 
be flagged.
Each ECG parameter will be summarized by treatment, visit/time using statistics like N, mean, 
median, standard deviation, and range.
The same data will be plotted using arithmetic mean-SD graphs over time for each parameter 
separately. Separate lines will be drawn for each treatment in order to see any potential 
differences. Reference lines will be drawn for normal ranges (if available).
Clinical laboratory evaluations
All laboratory data (hematology, blood chemistry, urinalysis) will be listed by treatment, 
subject, and visit/time and if normal ranges are available abnormalities will be flagged.
Each laboratory parameter (hematology, blood chemistry, urinalysis) will be summarized by 
treatment, visit/time using statistics like N, mean, median, standard deviation, and range.
The same data (hematology, blood chemistry, urinalysis) will be plotted using arithmetic 
mean-SD graphs over time for each parameter separately. Separate lines will be drawn for 
each treatment in order to see any potential differences. Reference lines will be drawn for 
normal ranges (if available).
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment.
Furthermore, risk ratio of LML134 compared to placebo along with 95% confidence interval 
will be drawn in a forest-plot for each system organ class and preferred term.


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An adverse event starting in one epoch and continuing into the next epoch is counted only in 
the onset period. A subject with multiple adverse events within a body system and treatment 
epoch is only counted once towards the total of this body system and treatment.
Other safety evaluations
All safety data will be listed by treatment, subject, and visit/time. Summary statistics for 
specific parameters will be reported based on clinical decision. Details of reporting will be 
mentioned in SAP.
Analysis of PSG data will be discussed in detail in SAP.
11.5.3
Pharmacokinetics
Analysis will be performed under PK analysis set.
LML134 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ and reported as 
zero.
Conventional PK parameters will not be calculated due to the limited sampling schedule. 
However, plasma concentrations will be listed and summary statistics for concentrations will 
be provided for plasma. The data will be part of the over-all Population PK model.
Concentrations below the LLOQ will be treated as zero in summary statistics for 
concentration data only. They will not be considered for calculation of PK Parameters 
(with the exception of the pre-dose samples).
11.5.4
Pharmacokinetic / pharmacodynamic interactions
Not applicable.
11.5.5
Other assessments
Not applicable.
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ate
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11.7
Sample size calculation
It is planned to have data for 36 subjects with evaluable results under the primary endpoint 
without any major protocol deviations. Assuming a 20% drop-out rate we expect to enroll 
approximately 46 subjects. In case there will be less than 36 evaluable subjects additional 
subjects may be enrolled. 
Based on Czeisler et al 2005 a 2 minute increase in primary endpoint for SWD patients 
compared to placebo is considered to be the ‘true effect’. Furthermore a SD of 4 minutes and 
a 20% drop out rate is used based on other sleep disorder study experience.
Efficacy criteria:
a.
Statistical significance: A significant increase compared to placebo in sleep latency 
characterized by p-value < 0.1
And
b. At least 1 minute increase in MSLT sleep latency compared to placebo characterized by 
an estimated mean difference of > 1 minute
Sample size is evaluated based on a simulation exercise with an ANOVA model with 
treatment and period as fixed effects. The following operating characteristics are observed:
Table 11-1
Operating characteristics for dual criteria
True effect* (in mins)
Both criteria met (%)
Both criteria failed (%)
One of the criteria met (%)
1.0
41.3
50.0
8.7
1.2
49.7
41.6
8.7
1.5
62.2
29.8
8.0
1.7
69.9
22.9
7.2
2.0
80.0
14.4
5.6
2.2
85.4
10.2
4.5
2.5
91.5
5.6
2.9
* True effect: Change in MSLT (LML134X-Placebo)
Futility Analysis:
An interim analysis is planned at mid-way with 18 completers to evaluate the chance of 
attaining proof of concept at the end of the trial. A very low chance may result in early 
stoppage of the trial due to futility.
11.8
Power for analysis of key secondary variables
No power analysis was performed for secondary variables.
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
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12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.


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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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Toyota H, Dugovic C, Koehl M, et al (2002) Behavioral characterization of mice lacking 
histamine H(3) receptors. Mol. Pharmacol. p. 389-97.


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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase 
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
ALT or AST elevation with 
coagulopathy
ALT or AST elevation 
accompanied by symptoms
Isolated ALT or AST elevation 
> 8 × ULN
Jaundice
Isolated ALT or AST elevation 
> 5 to ≤ 8 × ULN

If confirmed, consider interruption or discontinuation of study 
drug

If elevation persists for more than 2 weeks, discontinue the 
study drug 

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if >50% 
is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance*


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Criteria
Actions required
Any AE potentially indicative of 
liver toxicity

Consider study treatment interruption or discontinuation 

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual
Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV RNA, 
IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV 
infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency

Alpha-1-antitrypsin


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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 
3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset glucosuria on urine dipstick (unless 
related to concomitant treatment, diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data load. 
Review and record possible contributing factors to 
the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures 
(MRI etc) in the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium, 
potassium, phosphate, calcium), bicarbonate 
and uric acid

Urine output
Monitor subject regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline 
or protein-creatinine ratio within 50% of 
baseline)
or

Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level 
with ±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause 
rather than tubular toxicity.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LML134
CLML134X2201
A randomized, subject and investigator-blinded, placebo 
controlled, cross-over, multi-center Proof of Concept (PoC) 
study to assess the wakefulness promoting effect, safety, 
tolerability, and pharmacokinetics of LML134 in shift work 
disorder (SWD) patients
Statistical Analysis Plan (SAP) Amendment V02
Document type:
SAP Documentation – NIBR 
Document status:
Final
Release date:
12-Dec-2018
Number of pages:
17
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis. 
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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of figures ......................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................6
1.3.1. Primary objective(s).......................................................................................6
1.3.2. Secondary objective(s)...................................................................................6
1.4
Study design and treatment......................................................................................7
2
First interpretable results (FIR) ...........................................................................................8
4
Statistical methods: Analysis sets........................................................................................9
5
Statistical methods for Pharmacokinetic (PK) parameters................................................10
5.1
Variables................................................................................................................10
5.2
Descriptive analyses ..............................................................................................10
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
6.1
Primary objective...................................................................................................11
6.1.1
Variables ...............................................................................................11
6.1.2
Descriptive analyses..............................................................................11
6.1.3
Statistical model, assumptions and hypotheses.....................................11
6.2
Secondary objectives .............................................................................................12
6.2.1
Variables ...............................................................................................12
6.2.2
Descriptive analyses..............................................................................12
6.2.3
Statistical model, assumptions and hypotheses.....................................13
7
Statistical methods for safety and tolerability data............................................................16
7.1
Variables................................................................................................................16
7.2
Descriptive analyses ..............................................................................................16
7.3
Graphical presentation...........................................................................................17
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List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................10
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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLML134X2201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
A study protocol (v04) is available at the time of finalization of Statistical Analysis Plan.
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1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives
! To demonstrate that wakefulness in 
SWD 
patients 
is 
significantly 
increased 
after 
treatment 
with 
LML134 compared to placebo
!
Average sleep latency over two
consecutive test nights as measured 
by the MSLT
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)
! To assess the safety and tolerability 
of LML134 compared to placebo in 
SWD patients
!
Standard safety assessments such as 
vital signs, ECG, hematology, blood 
chemistry, urinalysis, AE reporting, 
and daytime PSG to assess drug effect 
on sleep
!
To 
assess 
the 
plasma 
pharmacokinetics of LML134 in 
SWD patients
!
Due to sparse sampling, only plasma 
concentrations will be listed and no 
PK parameter will be evaluated by 
noncompartmental analysis. The data 
will be part of the overall Population 
PK model
!
To evaluate the time course of 
LML134 
effect 
on 
wakefulness 
compared to placebo
!
MSLT at each time point averaged 
over two consecutive test nights
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1.4
Study design and treatment
This is a randomized, subject and investigator-blinded, placebo controlled, crossover, multi-
center Proof of Concept (PoC) study with in-house simulated laboratory night shifts in patients 
with SWD. 
This non-confirmatory study will include two treatment arms: LML134 
 and placebo. 
The study will utilize a 2x2 crossover design, with two treatment periods and two sequences as 
shown in Figure 1-1 whereas assessment details are shown in Figure 1-2. 
Approximately 46 subjects were planned to be randomized in this study (to achieve 36 
completers). All subjects will receive both treatments (LML134 and placebo), one in each 
treatment period, with the order of treatment being randomized. The study is prematurely 
terminated based on business decision after 18 completers.
Figure 1-1 Study Design
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2
First interpretable results (FIR)
No first interpretable result (FIR) is planned for this study. All the results will be represented in 
clinical study report (CSR).
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4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analysed according to the actual study treatment(s) 
received. This is due to fact that it is known that a few subjects has been mis-randomized to a 
different treatment group as compared to the planned list of randomization. In order to make 
use of full data , all analysis will be performed on actual treatment group received by subject 
instead of a planned one.
The full analysis set will include all subjects that received any study drug and had any post-
baseline assessment.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
For subjects for which the actual sequence of treatments received does not match the 
randomized sequence of treatments, the actual sequence will be used for analysis involving a 
sequence component (e.g. ANOVAs with a sequence effect) if the actual sequence is one of the 
sequences planned in the study design. If the actual sequence is not one of the sequences 
planned in the study design, the randomized sequence will be used for analysis involving a 
sequence component but data points from periods in which the subject has not received the 
randomized treatment will be excluded from the analysis. 
Types of analysis/endpoints
Analysis set to be used
Demographics and baseline characteristics
Full analysis set
Analysis of safety data
Safety set
Analysis of PK data
PK set
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The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables 
LML134 plasma concentration will be the PK variable of interest for this study. Conventional 
PK parameters will not be calculated by noncompartmental analysis due to the limited sampling 
schedule. The data will be part of the overall Population PK model.
5.2
Descriptive analyses
LML134 plasma concentration data will be listed by treatment, subject, and sampling time point. 
Descriptive summary statistics will be provided by treatment and sampling time point.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, maximum, and the frequency (n, %) of concentrations below 
the LLOQ. Concentrations below LLOQ will be treated as zero in summary statistics. A 
geometric mean will not be reported if the dataset includes zero values.
Graphical methods will be employed to show mean and individual concentration-time profiles. 
For the plots, time will be defined as the hours post first-dose within each period.
6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the full analysis set will be included in the PD data analysis.


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6.1
Primary objective
The primary objective of this study is to demonstrate that wakefulness in shift work disorder 
(SWD) patients is significantly increased after treatment with LML134 compared to placebo.
6.1.1
Variables 
The mean of multiple sleep latency test (MSLT) scores is the primary variable of this study.
Each subject will undergo a sleep latency test assessment at each period, at approximately 1:30, 
3:30, 5:30 and 7:30 in Day 2 (Night 1) and Day 3 (Night 2) during Treatment Period 1 and same 
time points in Days 12 and 13 in Treatment Period 2. In total, a subject will have 8 sleep latency 
test assessments in each treatment period. The mean value of all the sleep latencies from a 
subject within a period will be defined as mean sleep latency score for that subject for that 
period.
No change from baseline comparison will be used as no baseline is collected due to the short 
duration of the study. 
6.1.2
Descriptive analyses
The primary variable will be listed by treatment sequence, patient and period, and descriptive 
statistics will be provided by treatment. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, maximum. 
Boxplots will be employed to present the MSLT results by treatment.
6.1.3
Statistical model, assumptions and hypotheses
MSLT from both periods will be included in the analysis.
 
 
 Due to high variability and time difference between 
screening MSLT and post treatment records, screening MSLT will not be used as a covariate
for modelling . Total sleep time from sleep diary data during baseline will be used as baseline 
covariate. Therefore both smoking status (nicotine intake) and total sleep time at baseline will 
be considered as covariates in the model.
The primary variable, mean MSLT of a subject within a period, will be analyzed using a 
mixed effect analysis of variance model. This model will have the mean MSLT as the 
dependent variable; treatment, actual treatment sequence, smoking status at screening, total 
sleep time at baseline, treatment interaction with total sleep time at baseline and smoking 
status and period as fixed effects and a subject level random intercept. Primary analysis will 
be assessed over full analysis set.
Least square estimates for each treatment (LML134 and placebo) and treatment difference 
(LML134 vs placebo) along with 95% confidence interval will be reported.
The following assessments will be performed to judge efficacy of LML134:
1. Statistical significance: One sided (superiority) p-value of LML134 vs placebo from 
above fitted ANOVA model will be reported.
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A p-value <0.1 will be considered as a positive sign for statistical significance.
2. Estimate of treatment difference (LML134 vs Placebo) will be reported.
An estimate of treatment difference > 1 minute would be considered as significant.
6.1.3.1
Handling of missing values/censoring/discontinuations
If a subject has missing data at any time-point at night 1(/2), then the missing observation will 
be imputed as average of observed values from nearest neighbourhood of that day. 
 
 
 
If all observations at a night are missing the 
values from other night will be used for MSLT evaluation.
6.1.3.2
Sensitivity analyses
Mean of multiple sleep latency test (MSLT) score is essentially a positive outcome. Thus, a 
supportive analysis will be performed using log transformed mean sleep latency scores. Log 
transformed mean sleep latency score data will be analysed using a mixed effect ANOVA 
model with treatment, actual treatment sequence, smoking status at screening, total sleep time 
at baseline treatment interaction with total sleep time at baseline and smoking status and 
period as fixed effects and subject as a random effect. Geometric means of each treatment and 
their ratio (LML134 vs placebo) along with 95% confidence intervals will be estimated using 
least square means by back transforming to the original scale.
A supportive analysis with may be performed with additional covariates (total sleep time on 
actigraphy during baseline, key PSG parameters at screening/baseline) that may potentially 
affect individual mean MSLT data. 
6.1.3.3
Supportive Analysis
Primary analysis as mentioned in section 6.1.3 may be performed in a bayesian platform with 
non-informative priors for both LML and placebo.
6.2
Secondary objectives
6.2.1
Variables 
The secondary variable is MSLT at each time point (1:30, 3:30, 5:30 and 7:30) separately, 
averaged over two consecutive test nights.
6.2.2
Descriptive analyses
MSLT
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The secondary variable will be listed by treatment sequence, patient, period and time, and 
descriptive statistics will be provided, by treatment and time. Summary statistics will include 
mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, 
maximum. 
An arithmetic mean +/- SD time profile (time-points: 1:30 AM, 3:30 AM, 5:30 AM, and 7:30 
AM) plot will be provided for each treatment. 
6.2.3
Statistical model, assumptions and hypotheses
MSLT
A mixed model repeated measure (MMRM) analysis of variance model, will be performed over 
mean sleep latency test (MSLT) scores with treatment, actual treatment sequence, period, time-
point, and treatment*time-point as fixed effects. A saturated covariance structure will be used 
for observations coming from same subject. If an unstructured covariance cannot be fitted 
simpler covariance structures will be examined. 
The overall treatment effect for LML134 vs placebo will be reported along with a 95% CI.
A line graph of means of MSLT with 95% CI over time may be provided .
A supportive analysis with may be performed with additional covariates (total sleep time on 
actigraphy during baseline, key PSG parameters at baseline/screening) that may potentially 
affect individual mean MSLT data. 
6.2.3.1
Handling of missing values/censoring/discontinuations
Please refer section 6.1.3.1 .
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7
Statistical methods for safety and tolerability data
All analysis will be performed under safety analysis set.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, AE and polysomnography (PSG) as well as subject demographics, 
baseline characteristics, and treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment and subject. 
Summary statistics will be provided for all subjects, as well as for each treatment.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment and subject.
Treatment
Data for study drug administration and concomitant therapies will be listed by treatment and
subject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and time.
Summary statistics of height, weight, temperature, blood pressure, and pulse rate will be 
provided by treatment and time using statistics like N, mean, median, standard deviation, and 
range.
ECG evaluations
All ECG data will be listed by treatment, subject and time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and time.
Each ECG parameter will be summarized by treatment, time using statistics like N, mean, 
median, standard deviation, and range.
The same data will be plotted using arithmetic mean-SD graphs over time for each parameter 
separately. Separate lines will be drawn for each treatment in order to see any potential 
differences. Reference lines will be drawn for normal ranges (if available).
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Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by treatment and
time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. 
Separate tables will be presented indicating event severity and study drug relationship.
An adverse event starting in one period and continuing into the next period is counted only in 
the onset period. A subject with multiple adverse events within a body system and treatment 
period is only counted once towards the total of this body system and treatment.
Polysomnography 
Polysomnography data will be listed by treatment, subject and time. Summary statistics will be 
provided by treatment and time.
Other safety evaluations
Columbia suicide severity rating, alcohol test, drug test, cotinine test, pregnancy and assessment 
of fertility data will be listed by treatment and time.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter, PSG) will 
be created.
ECG and vital signs data will also be plotted using arithmetic mean-SD graphs over time for 
each parameter separately. Separate lines will be drawn for each treatment in order to see any 
potential differences