Observational, Multicentre, Cross-sectional Study to Describe Diagnosis and Treatment Patterns in Narcolepsy Patients in Real Life Practice in Spain
Conditions: Narcolepsy
Sponsor: Takeda

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TAK-994-5001 
 
SOMNUS 
 
Study Protocol Version 1.0, 2 September 2020 
Page 1 of 55 
 
 
 
 
 
 
 
 
Non-Interventional Study Protocol 
 
Title: 
Observational, multicentre, cross-sectional study to describe diagnosis and 
treatment patterns in narcolepsy patients in real life practice in Spain.  
 
Short title: 
SOMNUS 
 
Study ID: 
TAK-994-5001  
 
Sponsor: 
Takeda Farmacéutica España S.A. 
C/ Paseo de la Castellana 95. Planta 22 
28046 - Madrid 
Phone: +34 917904330 
 
 
Study phase:  Medical Affairs, Post-Approval Company Sponsored (Observational) 
 
Date of final version of the protocol:  2 September 2020 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered. Furthermore, the information is only meant for review and compliance by the recipient, his or 
her staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
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1 
Administrative information 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
 
Issue 
Iberia Contact 
Serious adverse event and 
pregnancy reporting 
 
Takeda Farmacéutica España S.A. 
Edif. Torre Europa, planta 22 
Pº Castellana, 95.  
28046- Madrid (Spain) 
Tel: 
 
Email: farmacovigilancia@takeda.com 
 
 
Medical Monitor 
(medical advice on protocol, 
compound, and medical 
management of subjects) 
 
Takeda Farmacéutica España S.A. 
Edif. Torre Europa, planta 22 
Pº Castellana, 95  
28046- Madrid (Spain) 
Email: 
 
 
 
Takeda Farmacéutica España S.A. 
Edif. Torre Europa, planta 22 
Pº Castellana, 95  
28046- Madrid (Spain) 
Email: 
 
 
Dr. 
,  
  
Email: 
 
 
Dr. 
 
  
  
Email: 
 
 
 
 
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Responsible Medical Officer   
(carries overall responsibility 
for the conduct of the study) 
 
Takeda Farmacéutica España S.A. 
Edif. Torre Europa, planta 22 
Pº Castellana, 95  
28046- Madrid (Spain) 
Email: 
 
 
 
Takeda Farmacéutica España S.A. 
Edif. Torre Europa, planta 22 
Pº Castellana, 95  
28046- Madrid (Spain) 
Email: 
 
 
 
 
 
For non-commercial use only

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INVESTIGATOR SIGNATURE PAGE 
I confirm that I have read and that I understand this protocol and any other product information provided by the 
sponsor. I agree to conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
- 
The ethical principles that have their origin in the Declaration of Helsinki. 
- 
International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated Guideline. 
- 
All applicable laws and regulations, including, without limitation, data privacy laws and regulations. 
- 
Regulatory requirements for reporting serious adverse events as defined in this protocol. 
 
 
Signature of Investigator 
Date 
<Investigator Name (print or type)> 
<Investigator’s Title> 
<Location of Facility (City, State/Provence)> 
<Location of Facility (Country)> 
 
 
 
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STUDY SUMMARY 
 
Name of Sponsor(s): 
Takeda Farmacéutica España S.A. 
Compound/Product: 
Not Applicable 
Title of Protocol:  
Observational, multicenter, cross-sectional study to describe diagnosis and treatment patterns in narcolepsy 
patients in real life practice in Spain. SOMNUS Study 
Study Number: TAK-994-5001 
Phase: Non-Interventional 
Study Design: 
Observational, multicenter, cross-sectional study with retrospective medical chart review, conducted in public 
and private Spanish sleep clinics. 
Primary Objectives: 
The primary objective is to describe real-world management and treatment patterns in narcolepsy patients in 
Spain: 
 
To describe the treatment patterns of narcolepsy, including in patients with and without cataplexy 
(NT1 and NT2) 
Secondary Objectives: 
• 
Describe sociodemographic and clinical characteristics of patients with narcolepsy (including a 
description of these characteristics in both treated and treatment-naïve patients) 
• 
To describe which specialists are involved in diagnosis of patients with narcolepsy 
• 
To describe diagnosis processes used in real-world as described in patients’ medical records 
• 
To evaluate and describe real-life effectiveness (treatment outcomes) of the currently used narcolepsy 
treatments in the study period 
• 
To estimate utilization of health care resources associated with narcolepsy patients in Spain, in terms of 
treatment, number of visits, hospitalization, and additional resources  
• 
To estimate indirect costs associated with narcolepsy patients in Spain, using the Work Productivity and 
Activity Impairment Questionnaire General (WPAI-GH) 
• 
To describe the health-related quality of life (HRQoL) of patients with narcolepsy in Spain using the EQ-
5D questionnaire. 
• 
To assess the perception of stigma of patients with narcolepsy in Spain using the 8-item Stigma Scale for 
Chronic Illness (SSCI-8).  
• 
To describe treatment satisfaction of patients with narcolepsy in Spain using the Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) 
• 
To describe the burden of illness in terms of associated comorbidities and associated disorders 
• 
To describe adverse reaction associated to narcolepsy treatments 
Exploratory Objectives: 
• 
Identify the proportion of patients with narcolepsy (with and without cataplexy) diagnosed and managed 
in public hospitals in Spain 
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• 
Evaluate and describe the diagnosis and treatment management of patients with narcolepsy up to one 
year before diagnosis through medical chart review. 
• 
Describe utilization of health care resources associated with narcolepsy patients in Spain, before and after 
diagnosis of narcolepsy 
• 
In the patients treated for narcolepsy within the 1st year after diagnosis of narcolepsy; describe the 
differences in utilization of healthcare resources before and after treatment initiation 
Subject Population:  
Adult patients with confirmed diagnosis of narcolepsy (both type I and type II) defined by the International 
Classification of Sleep Disorders, Third Edition (ICDS-3) 
Sample Size: 
Approximately 196 patients will be included in the 
study: 137 type 1 and 59 type 2 narcolepsy patients. 
Study Sites:  
15 sites are estimated to participate (10 public and 
5 private) with expertise in the management of 
patients with narcolepsy 
Duration of Study: 
Overall Study Duration: 24 months (since site selection to final report) 
Enrolment period: 8 months 
Treatment / Follow-up: One Study Visit (1 day) 
Criteria for Inclusion: 
• 
Patient aged ≥18 years at the time of study inclusion  
• 
Patient with confirmed diagnosis of narcolepsy between 2014 to 2019 defined by the International 
Classification of Sleep Disorders, Third Edition (ICDS-3)  
• 
Patient with at least 1-year follow-up with data available at the participating site after initial 
narcolepsy diagnosis and before study inclusion. 
• 
Patients with data available at the participant site at least 1-year before narcolepsy diagnosis 
• 
Patient capable to fulfill the study questionnaires. 
• 
In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements. 
• 
The subject or, when applicable, the subject’s legally acceptable representative signs and dates a written, 
informed consent form and any required privacy authorization prior to the initiation of any study 
procedures.  
Criteria for Exclusion: 
• 
Patient with any serious degenerative disease (Alzheimer, Parkinson or epilepsy) or psychiatric condition  
• 
Any other reason that, in the Investigator's opinion, makes the patient unsuitable to participate in this 
study.  
• 
Patient participating in a clinical trial (≤12 months) 
Endpoints/Outcomes and Measures 
The primary objective is to describe real-world management and treatment patterns of narcolepsy patients in 
Spain: 
o Treatments (pharmacological and non-pharmacological) to be described and stratified by following 
groups: 
 
Patients with and without cataplexy 
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 
Patients treated and naïve patients 
Secondary endpoints for this study are: 
• 
Sociodemographic and clinical characteristics of narcoleptic patients collected in the study.  
• 
Specialists involved in diagnosis of patients with narcolepsy 
o 
Type of specialists who diagnoses narcolepsy patients in Spain 
• 
Diagnosis processes used in real-world as described in patients’ medical records 
o 
Different procedures or tests for the diagnosis of narcolepsy will be described: Clinical history, 
ESS, PSG, MSLT, types of HLA 
o 
Diagnosis processes for patients with narcolepsy in terms of time since first symptoms to 
diagnosis, time from diagnosis to first treatment to will be described. 
• 
Effectiveness (treatment outcomes) of the currently used narcolepsy treatments in the study period 
o 
Pharmacological treatments and interventions since diagnosis will be described: type and doses, 
dose adjustments and reason to modification, drug switching  
o 
Clinician assessment associated with each treatment received for narcolepsy will be described, 
stratifying by treatment used: if use of different scales: no/yes, specify Sustained Attention to 
Response Task (SART), Maintenance of Wakefulness Test (MWT), the Epworth Sleepiness 
Scale (ESS) and cataplexy scales(1). 
o 
Non-pharmacological treatment outcomes will be described: Take short naps; Maintain a regular 
sleep schedule; Avoid caffeine or alcohol before bed; Avoid smoking, especially at night; 
Exercise daily; Avoid large, heavy meals right before bedtime; Relax before bed.    
• 
Costs associated with direct and indirect healthcare resource use by narcolepsy patients in Spain: 
o 
Direct medical healthcare resources used by patients with narcolepsy in the 12 months after 
diagnosis of narcolepsy. Healthcare resources such as outpatient visits, tests performed, previous 
narcolepsy treatment, complication associated to narcolepsy, hospitalizations, and emergency 
room/department visits will be presented in terms of: 
 
percentage of patients using each healthcare resource 
 
resources used per patient/year (for each specific resource) 
o 
Indirect health resources will be described through 
 
the scores obtained in the Productivity loss, Absenteeism, Presenteeism, Disability 
(WPAI questionnaire) score at study visit. 
 
Ad-hoc questions related to occupational accidents 
• 
Health-related quality of life (HRQoL) of patients with narcolepsy in Spain:  
o 
Description of the scores obtained in the EQ-5D Questionnaire. 
• 
Perception of stigma in patients with narcolepsy in Spain: 
o 
Describe the level of stigmatization in patients with narcolepsy in the Stigma Scale chronic 
illnesses (SSCI-8)  
• 
Treatment satisfaction of patients with narcolepsy in Spain: 
o 
Description of the score obtained in the Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) 
• 
Burden of illness in terms of associated comorbidities and associated disorders since diagnosis: 
o 
Description (%) of comorbidities and other concomitant disorders will be described. 
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Statistical Considerations: 
Management and treatment patterns of patients with narcolepsy in Spain will be described in terms of patient´s 
characteristics and medications or drugs collected in the study period. 
The descriptive analysis will include number of patients with valid/missing observations, mean, standard 
deviation (SD), median, 25 and 75 percentiles (P25 and P75, respectively), minimum and maximum for 
continuous variables. 
All data will be analysed at global and different subgroups. 
Sample Size Justification:  
The main objective of this study is to describe treatment patterns of narcolepsy patients in Spain.  
Since it is an exploratory analysis, the sample size (N) will be calculated based on statistical criteria, using the 
criterion of maximum indetermination, when the percentage is expected to be around 50%.  
A sample of 196 evaluable patients is sufficient to estimate a population percentage of 50%, with a 95% 
confidence interval of ± 7 percentage units. With this sample size, the continuous variables will be estimated 
with an accuracy of ±0.071 standard deviations (SD).  
 
 
 
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Table of Contents 
 
1 
Administrative information................................................................................................................................... 2 
1.1 
Contacts ...................................................................................................................................................... 2 
1.2 
Approval ..................................................................................................................................................... 4 
2 
Introduction.......................................................................................................................................................... 14 
3 
Study Objective(s) and Endpoint(s)/Outcome(s) .............................................................................................. 16 
3.1 
Objective(s) .............................................................................................................................................. 16 
3.1.1 
Primary Objective .................................................................................................................. 16 
3.1.2 
Secondary Objective(s).......................................................................................................... 16 
3.1.3 
Exploratory Objective(s) ....................................................................................................... 16 
3.2 
Endpoint(s)/Outcome(s) .......................................................................................................................... 17 
3.2.1 
Primary Endpoint ................................................................................................................... 17 
3.2.2 
Secondary Endpoint(s)........................................................................................................... 17 
3.2.3 
Exploratory Endpoint(s) ........................................................................................................ 18 
4 
Study Methods ..................................................................................................................................................... 19 
4.1 
Study Schedule......................................................................................................................................... 19 
4.2 
Study Design ............................................................................................................................................ 19 
4.3 
Selection of Study Population................................................................................................................. 21 
4.3.1 
Inclusion Criteria.................................................................................................................... 21 
4.3.2 
Exclusion Criteria................................................................................................................... 22 
4.4 
Treatments ................................................................................................................................................ 22 
4.5 
Premature Termination or Suspension of Study or Study Site ............................................................. 22 
4.5.1 
Criteria for Premature Termination or Suspension of the Study......................................... 22 
4.5.2 
Criteria for Premature Termination or Suspension of Study Sites...................................... 22 
4.5.3 
Procedures for Premature Termination or Suspension of the Study or the Participation of 
Study Site(s) ........................................................................................................................... 23 
4.6 
Study Plan ................................................................................................................................................ 23 
5 
Study Administrative Structure .......................................................................................................................... 28 
5.1 
Study Sites................................................................................................................................................ 28 
5.2 
Sponsor Personnel.................................................................................................................................... 28 
5.3 
Contract Research Organisation (CRO) ................................................................................................. 28 
6 
Ethics .................................................................................................................................................................... 28 
6.1 
Ethical conduct of the Study ................................................................................................................... 29 
6.2 
Independent Ethics Committee / Institutional Review Board and Authorities IEC/ IRB ................... 29 
6.3 
Authorities ................................................................................................................................................ 29 
6.4 
Subject Information and Written Informed Consent ............................................................................. 30 
7 
Safety Reporting .................................................................................................................................................. 30 
7.1 
Definitions ................................................................................................................................................ 30 
7.2 
Collection and Recording of Adverse Events, Special Situation Reports and Product Quality Issues
................................................................................................................................................................... 32 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory Authorities ..... 33 
8 
Data Quality Control and Assurance.................................................................................................................. 33 
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8.1 
Quality Control ........................................................................................................................................ 33 
8.2 
Audit from Quality Assurance Unit........................................................................................................ 34 
8.3 
Inspection by IRB/IEC or Competent Authority ................................................................................... 34 
8.4 
Data Management .................................................................................................................................... 34 
8.4.1 
Data Collection Tools and Flow............................................................................................ 35 
9 
Statistical Methods and Determination of Sample Size .................................................................................... 35 
9.1 
Statistical Analysis Plan .......................................................................................................................... 35 
9.2 
General considerations ............................................................................................................................ 36 
9.2.1 
Evaluable patients .................................................................................................................. 36 
9.2.2 
Primary Endpoint ................................................................................................................... 36 
9.2.3 
Secondary Endpoint(s)........................................................................................................... 36 
9.2.4 
Exploratory Endpoint(s) ........................................................................................................ 39 
9.3 
Interim Analyses ...................................................................................................................................... 39 
9.4 
Determination of Sample Size ................................................................................................................ 39 
10 Reports ................................................................................................................................................................. 40 
11 Publication, Disclosure, and Clinical Trial Registration Policy ....................................................................... 40 
12 Archiving of Study Documentation ................................................................................................................... 40 
13 References............................................................................................................................................................ 41 
14 APPENDICES ..................................................................................................................................................... 43 
 
 
 
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APPENDICES 
 
 
Appendix 1: Case Report Form 
Appendix 2: Study Investigator Agreement  
Appendix 3: Ethics Committee Approval 
Appendix 4: Patient Information Sheet 
Appendix 5: Informed Consent Form 
Appendix 6: Economic Details  
Appendix 7: Productivity loss, Absenteeism, Presenteeism, Disability (WPAI questionnaire). 
Appendix 8: EQ-5D questionnaire 
Appendix 9: Stigma Scale chronic illnesses (SSCI-8) 
Appendix 10: Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
Appendix 11: Takeda AE Report Form 
 
 
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List of Abbreviations and Definition of Terms 
AE: 
 
Adverse Event 
ADR:  
Adverse Drug Reaction 
CA: 
 
Competent Authority 
CCI: 
 
Charlson Comorbidity Index 
CCSI:  
Core Company Safety Information 
CRF: 
 
Case Report Form 
CRO:  
Contract Research Organisation 
CSF:  
 
Cerebrospinal fluid 
CV: 
 
Curriculum Vitae 
eCRF:  
electronic Case Report Form 
DNS: 
 
Disrupted nighttime sleep 
EDS:  
 
Excessive daytime sleepiness 
GCP: 
 
Good Clinical Practice 
GPP: 
 
Good Pharmacoepidemiology Practices 
HLA:  
Human leucocyte antigen 
HRQoL: 
Health-related quality of life 
ICH: 
 
International Conference on Harmonisation 
IDS: 
 
International Drug Safety 
IEC: 
 
Independent Ethics Committee 
ICSD-3: 
International Classification of Sleep Disorders  
IRB: 
 
Institutional Review Board 
MSLT:  
Mean sleep latency 
NREM:  
non-REM  
NT1: 
 
Narcolepsy type 1  
NT2: 
 
Narcolepsy type 2 
PSG: 
 
Polysomnography  
PSUR:  
Periodic Safety Update Report 
REM:   
Rapid eye movement 
SAE: 
 
Serious Adverse Event 
SAP: 
 
Statistical Analysis Plan 
SADR:  
Serious Adverse Drug Reaction 
SOREMPs: 
Multiple sleep-onset REM periods 
SPC: 
 
Summary of Product Characteristics 
 
 
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2 
Introduction 
Narcolepsy, a rare chronic primary sleep disorder, for which no cure has been identified. Global prevalence of 
narcolepsy is 25–50 cases per 100,000 individuals(2) and affects 4.7 of 10.000 (0.047%) individuals in the 
European general population(3). Its prevalence is low, mainly because the long diagnostic delay (with 
approximately 50% of patients waiting 6 to 10.5 years to receive an accurate diagnosis) what could cause an 
underestimation of its prevalence(4, 5).  
The typical onset of narcolepsy is during adolescence and early adulthood and it´s symptomatology is 
characterized by consensus on the five core symptoms: excessive daytime sleepiness (EDS) with symptoms of 
rapid eye movement (REM), with/without cataplexy ((muscle weakness), sleep paralysis, sleep-related 
(hypnagogic and hypnopompic) hallucinations, and disrupted nighttime sleep (DNS)  with excessive daytime 
sleepiness and cataplexy being the most common symptom(6).  
The establishment of hypocretin deficiency as the cause of narcolepsy made necessary to modify and redefine the 
terminology used to define the two subtypes of narcolepsy in the 3rd Edition of the International Classification of 
Sleep Disorders (ICSD-3):  
- 
Narcolepsy type 1 (NT1), the most frequent type, caused by a loss of the hypothalamic hypocretin-
producing neurons, and cataplexy as its distinctive symptom. It has a tight association with the human 
leucocyte antigen (HLA) DQB1*0602 allele and therefore an immune-mediated aetiopathogeny is 
hypothesized.  
- 
Narcolepsy type 2 (NT2) in which EDS is associated with reduced mean sleep latency (MSLT) and 
multiple sleep-onset REM periods (SOREMPs) in the MSLT, but cataplexy is absent and levels of 
hypocretin 1 are normal.  
But, although hypocretin deficiency is the hallmark of narcolepsy type 1, the relative unavailability of hypocretin 
assays to date has a result the continuation of the identification of cataplexy to establish a narcolepsy type 1 
diagnosis. 
Narcolepsy symptoms can often be confused and mimicked by other sleep disorders or overlap with psychiatric 
symptomology, what difficult the correct diagnosis.  As well as the absence of easily measurable biomarkers. This 
indicates that more specific diagnostic procedures should be incorporated (detailed presenting history, assessment 
of sleep-wake cycles and sleep deprivation, subjective (sleep diary) and objective testing (polysomnography 
(PSG), actigraphy, MSLT including drug-testing of urine, human leukocyte antigen (HLA) typing and lumbar 
puncture to measure CSF hypocretin-1 (orexin) levels)(7).  
Currently there is no cure for narcolepsy so current treatments for narcolepsy are based on symptomatic 
management, basically of sleepiness and cataplexy. Patients with narcolepsy require not only pharmacological 
treatment (actually there are three main pharmacological drugs for narcolepsy treatment: stimulant for EDS, 
antidepressants for cataplexy and sodium oxybate for symptoms), but mainly behavioral modifications such as a 
regular night-time sleep schedule, avoiding sleep deprivation, short scheduled naps, diet, work and school 
accommodations, and sometimes, psychotherapy(8). It has been described that medication in combination with 
lifestyle changes helps returns approximately 80% of patients with narcolepsy back to near normal functioning. 
Recent advances in the understanding of the neurobiological basis of narcolepsy have led to the investigation of 
novel treatment options(9). Current recommended therapies for narcolepsy act on several neurotransmitters but 
do not target the cause of the disorder, just aim to manage selective symptoms with inconsistent efficacy, leaving 
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others untreated(10). And medications are prescribed based on, mainly, the following symptom: EDS and sleep 
attacks; disturbed nighttime sleep, and; cataplexy, hypnagogic hallucinations, and sleep paralysis(8, 11). 
 Measuring the severity of the narcolepsy symptoms and treatment efficacy became a major outcome in 
management optimization. It´s also known that dose adjustment, switching to another drug, and prescription of 
multiple medications are often required when managing narcolepsy in the long term(6).  
On the other hand, comorbidities live together with narcolepsy, and sometimes is difficult to know where  
narcolepsy end and comorbidities begin.  Treatment of comorbidities is unfortunately often neglected but can be 
really important for some patients. Attention to comorbidities is important in the comprehensive management of 
patients with narcolepsy(12). 
Although the prevalence of narcolepsy is low, the associated healthcare costs are disproportionately high, with 
direct medical and pharmacy costs that are twice that of the general population(13). Narcolepsy has no known 
cure, requires lifelong treatment, diagnosis is delayed, and all increase its economic burden: increased medical 
costs relative to the general population, an increased risk for work-related or vehicular accidents, and reduced 
quality of life. Considering the substantial burden of this disease, improvement in a patient’s quality of life (QoL) 
and ability to function in daily work and other activities are critically important(14). 
Patients with narcolepsy often present comorbid conditions including cardiometabolic comorbidities (e.g. obesity, 
type 2 diabetes, sleep apnea, cardiovascular diseases), neuropsychiatric comorbidities (e.g. mood disorders, 
anxiety, eating disorders and attention-deficit hyperactivity disorder), and other sleep disorders such as restless 
legs syndrome, periodic leg movements, REM and non-REM (NREM) sleep parasomnias(15-17). Thus, a 
substantial economic burden, is evidenced by higher healthcare utilization and costs related to the treatment of 
these comorbidities, inpatient, outpatient, emergency department, and prescription costs(18). It has also been 
associated with a negative impact on work productivity including increased unemployment, elevated rates of long-
term disability, absenteeism, and presenteeism, early retirement, accidents at work, welfare enrollment, general 
impairment at work, and lower wages(19). 
On the other hand, narcolepsy is heavily associated with a substantial adverse impact on mental health and health-
related quality of life (HRQoL), including the domains of mood, psychopathology, and other areas such as marital 
and work problems(20). It´s well described the problems faced by patients with narcolepsy with social stigma, 
difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. 
Besides, the late diagnosis adds to the substantial societal burden, not only at the time of diagnosis and after but 
also before the diagnosis(18).  
Given the limited real-world data available on treatment patterns of care, prevalence and health care resource 
utilization in patients narcolepsy NT1 and NT2), descriptive data in routine clinical practice would be desirable 
to improve the knowledge and the management of HR+/Her2-mBC 
It´s important to understand the epidemiology of the narcolepsy in Spain, as well as to correctly identify NT1 and 
NT2 patients and how these patients are being managed in routine clinical practice given the lack of information 
published in our country. 
The current observational study aims to obtain real-world data on the characteristics and current management of 
NT1 and NT2 patients in a real-world setting. 
 
 
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3 
Study Objective(s) and Endpoint(s)/Outcome(s) 
 
3.1 
Objective(s) 
The study aims to provide a comprehensive overview of the real-world management and treatment patterns of 
narcolepsy in adults’ patients in real world practice in Spain.  
3.1.1 Primary Objective  
The primary objectives of the study are: 
o To describe the treatment patterns of narcolepsy between different subgroups, including:  
 
Patients with and without cataplexy 
 
Patients treated and naïve-treatment patients 
3.1.2 Secondary Objective(s) 
• 
To characterize sociodemographic and clinical characteristics of patients with narcolepsy and compare it 
between treated and untreated patients. 
• 
To describe specialists involved in diagnosis of patients with narcolepsy. 
• 
To describe diagnosis processes used in real-world as described in patients’ medical records. 
• 
To evaluate and describe effectiveness (treatment outcomes) of the currently used narcolepsy treatments in 
the study period. 
• 
To estimate direct costs associated with narcolepsy patients in Spain, in terms of treatment, number of visits, 
hospitalization, and additional resources in the last 12 months. 
• 
To estimate indirect costs associated with narcolepsy patients in Spain, using the Work Productivity and 
Activity Impairment Questionnaire General (WPAI-GH). 
• 
To describe the health-related quality of life (HRQoL) of patients with narcolepsy in Spain using the EQ-5D 
Questionnaire. 
• 
To assess the perception of stigma of patients with narcolepsy in Spain using the 8-item Stigma Scale for 
Chronic Illness (SSCI-8).  
• 
To describe treatment satisfaction of patients with narcolepsy in Spain using the Treatment Satisfaction 
Questionnaire Medication (TSQM-9). 
• 
To describe the burden of illness in terms of associated comorbidities and associated disorders in the last 12 
months. 
• 
To describe adverse reaction associated to narcolepsy treatments 
3.1.3 Exploratory Objective(s) 
• 
Identify the proportion of patients with narcolepsy (with and without cataplexy) diagnosed and managed in 
public hospitals in Spain. 
• 
Evaluate and describe the diagnosis and treatment management of patients with narcolepsy up to one year 
before diagnosis (this objective will be assessed through medical chart review). 
• 
Describe utilization of health care resources associated with narcolepsy patients in Spain, before and after 
diagnosis of narcolepsy 
• 
In the patients treated for narcolepsy within the 1st year after diagnosis of narcolepsy; describe the differences 
in utilization of healthcare resources before and after treatment initiation 
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3.2 
Endpoint(s)/Outcome(s) 
 
3.2.1 Primary Endpoint   
The primary objective is to describe real-world management and treatment patterns of narcolepsy patients in 
Spain: 
o A description of the different treatments (pharmacological and non-pharmacological) will be described 
and compared between the following groups: 
 
Patients with and without cataplexy 
 
Patients treated and treatment-naïve patients 
3.2.2 Secondary Endpoint(s) 
• 
A description of all sociodemographic and clinical characteristics of patients with narcolepsy collected in 
the study. The following groups will be compared: 
o 
Treatment-naïve patients and treated patients 
o 
To describe specialists involved in diagnosis of patients with narcolepsy 
 
A description of specialists who diagnoses narcolepsy patients in Spain 
• 
To describe diagnosis processes used in real-world as described in patients’ medical records 
o 
Clinical History 
o 
A description of the different procedures or tests for the diagnosis of narcolepsy will be described: 
clinical history, (absence/presence of cataplexy, number of cataplexy attacks, number of sleep-onset 
REM periods (SOREMPs),absence/presence of apneas and /or Apnea-hypopnea index (AHI),  
hipocrexine levels, ESS, PSG, MSLT and types of HLA. 
o 
Diagnosis processes for patients with narcolepsy in terms of time since first symptoms to diagnosis, 
time from diagnosis to first treatment to will be described. 
• 
To evaluate and describe clinician assessments (effectiveness) of the currently used narcolepsy treatments 
in the study period: 
o 
Pharmacological treatments and interventions since diagnosis will be described: type and doses, dose 
adjustments and reason to modification, drug switching, adverse events related to treatments  
o 
The outcomes associated with each treatment received for narcolepsy will be described, stratifying 
by treatment used: if any scale used for the outcomes and specify: Sustained Attention to Response 
Task (SART), Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). 
o 
Non-pharmacological treatment outcomes will be described: Take short naps; Maintain a regular 
sleep schedule; Avoid caffeine or alcohol before bed; Avoid smoking, especially at night; Exercise 
daily; Avoid large, heavy meals right before bedtime; Relax before bed.    
• 
To estimate the costs associated with direct and indirect healthcare resource use by narcolepsy patients in 
Spain: 
o 
Direct medical healthcare resources used by patients with narcolepsy in the last 12 months before 
study visit. Healthcare resources such as outpatient visits, tests performed, previous narcolepsy 
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treatment, complication associated to narcolepsy, hospitalizations, and emergency room/department 
visits will be presented in terms of: 
 
percentage of patients using each healthcare resource 
 
resources used per patient/year (for each specific resource) 
o 
Indirect health resources will be described though: 
 
the scores obtained in the Productivity loss, Absenteeism, Presenteeism, Disability 
(WPAI questionnaire) score at study visit.  
 
Ad-hoc questions at study visit related to occupational accidents. 
• 
To describe the health-related quality of life (HRQoL) of patients with narcolepsy in Spain:  
o 
Description of the scores obtained in the EQ-5D Questionnaire. 
• 
To assess the perception of stigma in patients with narcolepsy in Spain: 
o 
To know the level of stigmatization of patients with MS the score in the SSCI-8 will be described.  
• 
To describe treatment satisfaction of patients with narcolepsy in Spain: 
o 
Description of the score obtained in the Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) 
• 
To describe the burden of illness in terms of associated comorbidities and associated disorders: 
o 
Description (%) of comorbidities and other concomitant disorders will be described. 
• 
To describe adverse reaction associated to narcolepsy treatments 
o 
Describe type of adverse events reported  
3.2.3 Exploratory Endpoint(s)  
• 
Identify the proportion of patients with narcolepsy (with and without cataplexy) diagnosed and managed in 
public hospitals in Spain: 
o 
Description (%) of total number of patients with narcolepsy attended in the participating site 
according to routine clinical practice with at least 12-months follow up after over total population 
under the hospital’s circumscription. 
• 
Evaluate and describe the diagnosis and treatment management of patients with narcolepsy up to one year 
before diagnosis assessed through medical chart review. 
o 
Percentage (%) of treatments received for narcolepsy in the year before narcolepsy diagnosis will be 
described. 
o 
Percentage (%) and type of diagnosis received before narcolepsy diagnosis will be described 
• 
Describe utilization of health care resources associated with narcolepsy patients in Spain, before and after 
diagnosis of narcolepsy 
o 
Description (quantity and type) of healthcare resources associated with narcolepsy patients before 
and after being diagnosed for this condition.  
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• 
Describe utilization of health care resources associated with narcolepsy patients in Spain, before and after 
treatment for narcolepsy 
o 
In those patients that received treatment within the 1st year after diagnosis of narcolepsy: Description 
(quantity and type) of healthcare resources associated with narcolepsy patients before and after 
receiving treatment for this condition 
4 
Study Methods 
This study is a ‘non-interventional study’ as defined in Directive 2001/20/EC and will follow the guidelines for 
GPP. 
This means that: 
• 
The assignment of a subject to a particular therapeutic strategy is not decided in advance by the study protocol 
but falls within current practice. 
• 
No additional diagnostic or monitoring procedures shall be applied to the subjects. 
• 
Epidemiological methods shall be used for the analysis of collected data. 
4.1 
Study Schedule 
• 
Planned Start of Study: 
 
 
November 2020 
• 
Planned collection of first data point:  
November 2020 
• 
Planned End of Study:  
 
 
September 2021 
• 
Planned collection of the last data point: 
July 2021 
• 
Planned completion of the Study Report: 
December 2021 
The Start of Study is defined as date of first informed consent signed and the End of study is defined as last 
information of last subject included in the study is recorded in the database. 
The Sponsor will ensure that End-of-Study notification is submitted to the concerned authorities and IEC/IRB 
for each site and for the complete study, as locally required. 
The Sponsor will ensure that results are made publicly available as required by local authorities.  
Based on upcoming knowledge, the Sponsor might choose to terminate the study prematurely. In such case study 
sites, IECs/IRBs and authorities will be informed promptly. 
4.2 
Study Design   
A multicenter, non-interventional, cross-sectional, study with retrospective medical chart review, conducted in 
public and private Spanish institutions has been designed to describe the management of narcolepsy in adults’ 
patients in real world practice in Spain.  
The study will be conducted in a single visit, considering a fieldwork period of approximately 8 months to enroll 
all patients. This period could be extended if due to causes unrelated to the study (for example, a re-outbreak of 
COVID-19) the expected sample was not reached during that time. 
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The patient will be enrolled in one of the two study cohorts according to the type of narcolepsy at the time of the 
visit and after patient informed consent is obtained:  
Cohort A: type 1 narcolepsy patients 
Cohort B: type 2 narcolepsy patients   
Patients will attend a single visit where they will answer study questionnaires and some clinical variables will be 
collected from clinical records. In the event of a possible outbreak of COVID-19 that makes it necessary to replace 
face-to-face visits in the participating centers with telematic visits, both the informed consent and the study 
questionnaires will be collected remotely so as not to interfere with the development of the present study. 
Data will be collected: 
o Retrospective Period: patient should have at least 1 year of follow-up before narcolepsy 
diagnosis and must have been diagnosed of narcolepsy between 2014 and 2019, having at least 
1 year of follow-up before study visit. 
o Study visit: Clinical and demographic data and PRO will be collected from the patient during 
the study visit, respectively. 
 
Figure 1 illustrates the 3 study periods and timelines for data collection. 
Figure 1. Study Diagram 
 
• 
Index Period will be the period in which patient is diagnosed of narcolepsy, between 2014 and 2019. 
• 
Post-Index will be the at least a 1-year period before study visit all patients must have for the collection 
of use of resources in the last year 
• 
Pre-Index period will 12 months before diagnosis (for the exploratory objective) 
 
 
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Data source: 
The study variables will be recorded in an electronic case report form (eCRF) specially designed for the study 
eCRFs. The degree of detail and completeness of data collected is dependent on local clinical practice.  
Patient Recorded Outcomes (PROs) will be completed by patients in paper/electronic questionnaires and recorded 
in the corresponding section of eCRF. In the event of a possible outbreak of COVID-19 that makes it necessary 
to replace face-to-face visits in the participating centers with telematic visits, the study questionnaires will be 
collected remotely so as not to interfere with the development of the present study. 
Variables collected at the time of the study visit will be obtained based on and limited to those available in the 
medical records of the selected patients and only those according to standard clinical practice. 
To identify the proportion of patients with narcolepsy (with and without cataplexy) diagnosed and managed in 
public and private hospitals in Spain (exploratory objective of prevalence), secondary data will be collected from 
data included in the hospital (proportion of patients with narcolepsy with and without cataplexy managed at 
hospital level in the participant centers).  
4.3 
 Selection of Study Population 
Target population will be patients with confirmed diagnosis of narcolepsy defined by the International 
Classification of Sleep Disorders, Third Edition (ICDS-3), up to 7 years before study inclusion. 
Patients will be recruited consecutively as they go to the hospital: approximately 10 patients per site will be 
included. 
Patients will be invited to participate in this study during a routine medical visit for any purpose with their 
physician and the patient will be considered included when he/she agrees to participate in the study by signing the 
informed consent and if all of the following criteria are met. All included patients will attend a single visit. In the 
event of a possible outbreak of COVID-19 that makes it necessary to replace face to face visits in the participating 
centers with telematic visits, the invitation to participate, the obtention of patient's informed consent and the 
collection of patient's questionnaires will be carried out remotely. 
4.3.1 Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to inclusion into the study: 
1. Patient aged ≥18 years at the time of study inclusion  
2. Patient with confirmed diagnosis of narcolepsy between 2014 to 2019 defined by the International 
Classification of Sleep Disorders, Third Edition (ICDS-3)  
3. Patient with at least 1-year follow-up with data available at the participating site after initial narcolepsy 
diagnosis and before study inclusion. 
4. Patients with data available at the participant site at least 1-year before narcolepsy diagnosis 
5. Patient capable to fulfill the study questionnaires. 
6. In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements. 
7. The subject or, when applicable, the subject’s legally acceptable representative signs and dates a written, 
informed consent form and any required privacy authorization prior to the initiation of any study 
procedures. 
 
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4.3.2 Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. Any other reason that, in the Investigator's opinion, makes the patient unsuitable to participate in this study.  
2. Patient participating in a clinical trial (≤12 months*) 
3. Patient with any serious degenerative disease (Alzheimer, Parkinson or epilepsy) or psychiatric condition  
*Clinical trial participation could be cause of bias regarding healthcare resource use data collection. 
Subjects should be included in the study only once.  
Data erroneously collected from subjects for which written consent is not available, will not be included in or 
will be deleted from the database. 
4.4 
Treatments 
Non-interventional treatments/pharmacotherapy are instructed by the study protocol. 
4.5 
Premature Termination or Suspension of Study or Study Site 
4.5.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are satisfied that require 
temporary suspension or early termination of the study. 
• The Data Monitoring Committee or the Sponsor recommends that the study should be suspended or 
terminated. [if applicable] 
• Significant violation of Good Clinical Practice (GCP/GPV) that compromises the ability to achieve the 
primary study objectives or compromises subject safety. 
• The sponsor has the right to close the study with serving a preliminary written notice to investigators and 
hospitals. The sponsor has the right to unilaterally stop at any time enrolment of patients and/or gathering of 
data in the study with serving a preliminary written notice thereof on the Investigator indicating the date of 
stop of enrolment. The sponsor should ensure that notification about premature termination or suspension of 
the study is submitted to the concerned authorities and IEC.  
• The investigator has the right to stop recruitment at any time with serving a preliminary written notice to the 
Sponsor/responsible CRO. 
• In case of premature closure of the site/termination of the study, all completed and also unused (including the 
unused pages of partially completed CRFs) CRFs and all documentation forms (except documentation that has 
to remain stored at site) must be returned to the Sponsor, even unused ones. Study material may be destroyed 
only with permission of the Sponsor. 
4.5.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) is found in 
significant violation of GCP/GPP, protocol, or contractual agreement, is unable to ensure adequate performance 
of the study, or as otherwise permitted by the contractual agreement. 
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• Treatment Satisfaction Questionnaire for Medication (TSQM-9)(24): The 14-item treatment satisfaction 
questionnaire for medication (TSQM-14) was developed and validated as a general measure of satisfaction 
with treatment. It is a reliable and valid instrument to evaluate patient satisfaction with medication, 
providing scores on four scales: side effects, efficacy, convenience and overall satisfaction. A naturalist 
study concluded that the administration of the TSQM-14, which includes the side effects domain, can 
interfere with regular clinical practice. As a result, a shorter 9-item questionnaire was created, the TSQM-
9, derived from the TSQM-14, but without the five items in the side effects domain. The TSQM-9 has been 
recently validated to evaluate patient satisfaction with any kind of medication in observational naturalistic 
studies in the cardiovascular area; it is not specific for any disease and/or risk factor and has been used in 
Spanish of Spain. 
EXPLORATORY INFORMATION 
Prevalence and incidence 
• Total population under the hospital’s circumscription 
At least 12-months follow up after diagnosis: 
• Total of patients with narcolepsy attended in the participating site 
according to routine clinical practice and type of narcolepsy 
• New patients with narcolepsy diagnosed per year (incidence) 
Treatment management 
before diagnosis 
Up to 12-months before diagnosis  
• “narcolepsy-related” medication  
• Other medication “non-narcolepsy-related” 
• number of patients with at least one prescription in the 12 months pre-
index 
• Diagnosis pattern prior to the diagnosis of narcolepsy 
Utilization of health care 
resources before diagnosis of 
narcolepsy 
The last 12 months before diagnosis of narcolepsy: 
• Number of routine monitoring visits (specialists involved, tests 
conducted, treatment variations) since diagnosis up to study visits 
• Number of emergency visits (specialists involved, tests/procedures 
conducted, treatment administered) after diagnosis 
• Number and duration of hospitalizations 
• Differences in utilization of healthcare resources before and after 
diagnosis of narcolepsy 
• In the patients treated for narcolepsy within the 1st year after diagnosis of 
narcolepsy; differences in utilization of healthcare resources before and 
after treatment initiation 
 
 
 
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5 
Study Administrative Structure 
5.1 
Study Sites 
The study is planned to be conducted in approximately 15 Spanish sites: 10 public and 15 private institutions with 
expertise in the management of patients with narcolepsy.  
As a pre-study activity, sites will need to answer a site feasibility questionnaire in order to determine that the site 
has adequate facilities and investigator is qualified and meets the needs of the study, recruitment targets, quality 
and timelines in compliance with the applicable regulatory requirements. 
The Sponsor will keep a record of the individuals responsible for each participating Study Site, the Site 
Responsibles. 
5.2 
Sponsor Personnel 
 The Sponsor will keep a record of all relevant sponsor personnel. This record will include the Sponsor 
Coordinating Study Managers, local Study Managers and other medical staff, medical responsible for the study, 
drug safety responsible for the study.  
5.3 
Contract Research Organisation (CRO) 
The CRO, will be responsible of the following regulatory activities: 
- 
Regulatory activities: preparing, signing and submitting documents required by the applicable local 
ethics committees, central ethics committees and regulatory authorities and other local regulatory bodies 
when applicable,  
- 
Study implementation and initiation, study conducting and study close-out 
- 
Data management and project management 
- 
Making payments on Sponsor´s on behalf to institutions, investigators and other staff members related 
to the conduct of the study 
- 
Statistical analysis, elaboration of Statistical Analysis Plan (SAP) 
The CRO will keep a record of all involved CRO personnel. 
6 
Ethics 
This study is an observational study where the existence of the study has no impact on the subject except for 
collection of informed consent to use of the subject’s data.  
Patients will complete some questionnaires /PROs and the CRO will ask for the permission of use and will be 
included as part of the protocol for their evaluation and approval. 
In the event of a possible outbreak of COVID-19 that makes it necessary to replace face-to-face visits in the 
participating centers with telematic visits, both the informed consent and the study questionnaires will be collected 
remotely so as not to interfere with the development of this study. Once the situation is normalized, the patient 
will be asked to give consent again, and the doctor must record the date of signing the consent in the patient's 
record. 
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6.1 
Ethical conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the Declaration of Helsinki, 
Good Pharmacoepidemiology Practices (GPP), ISPE GPP guideline and according to Spanish SAS 
Order/3470/2009 of December 16 of the Ministry of Health and Social Policy which publishes the guidelines on 
observational post-authorization studies for medicinal products for human use, and the local laws and regulations. 
Special attention will be paid to data protection law: Ley Orgánica 3/2018, de 5 de diciembre, de Protección de 
Datos Personales y garantía de los derechos digitales 
The Sponsor and/or the appointed CRO will ensure that the protocol, any amendments and the Subject Information 
Sheet/Informed Consent Form are submitted to the relevant Independent Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) according to local requirements. 
The sponsor is responsible for meeting the International Conference on Harmonisation (ICH) requirement for 
yearly updates to the IECs/IRBs, if applicable. 
6.2 
Independent Ethics Committee / Institutional Review Board and Authorities IEC/ 
IRB 
According to applicable regulations, the appointed CRO or the Site Study Responsible will: 
• 
notify or obtain approval from the relevant IEC/IRB of the protocol, any amendments and the Subject 
Information Sheet / Informed Consent Form and questionnaires and Questionnaires 
The appointed CRO or the  Study Responsible will submit required documents to the IEC / IRB, such as: 
• 
periodic updates on the progress of the study 
• 
notification of the end-of-study 
• 
a summary of the study results 
The Sponsor or the responsible CRO will supply relevant documents for submission to the Independent Ethic 
Committee for the protocol's review and approval. This protocol, amendments to the protocol, the informed 
consent form, and other documents required by all applicable laws and regulations, must be submitted to a central 
IEC for approval. The IRB's or IEC's written approval of the protocol and patient informed consent must be 
obtained and submitted to the sponsor or the responsible Contract Research Organisation before start of the study. 
Documented approval from central IECs will be obtained for all participating investigational sites (principle 
investigators) prior to the study start. 
The Sponsor or the appointed CRO will keep an updated list of all submission and approval dates of all documents 
submitted to the IEC / IRB and will provide the Site Responsible with a copy of this list. Copies of the documents 
will be distributed upon request. 
6.3 
Authorities 
The Sponsor or the appointed CRO will send required documents to the competent authority (CA) and/or other 
national or regional authorities when applicable. The Sponsor or the appointed CRO will keep an updated list of 
submission and approval dates and a copy of all documents submitted.   
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6.4 
Subject Information and Written Informed Consent 
The Site Study Responsible must give the subject (and if applicable, parent or legal guardian) oral and written 
information about the study in a form that the subject (and if applicable, the parent or legal guardian) can 
understand, and obtain the subject’s (and if applicable, the subject’s assent and the parent’s or legal guardian’s) 
written consent before collection of identifiable subject information (hereinafter referred to as personal data). 
Before consenting, the subject (and if applicable, parent or legal guardian) must be left with ample time to consider 
and to pose questions. Since the study is observational the consent only concerns the data collection per se and is 
not consent to any interventional procedure or treatment.  
The subject must agree that sponsor personnel, their representatives or IEC/IRB or CA personnel (national or 
other) may require direct access to the subject’s data / personal records which were collected, processed and stored 
in an anonymous form.   
The subject must agree that his / her data will be processed and stored in an anonymous form for evaluation of 
this study and any later overviews. Data may also be transferred in anonymous form to third parties, e.g., to other 
companies or authorities, that may be located in other countries with potentially different regulations for data.  
However, in the event of a recurrence of COVID-19 that requires the replacement of routine face-to-face visits at 
the health center with telematic visits as part of routine clinical practice, both the invitation to participate in the 
study and the obtention of consent informed and the completion of the study questionnaires will be done remotely. 
Once the situation is normalized, the manual signature of the informed consent of each patient who has agreed to 
participate remotely will be collected. 
The subject and subject’s parent or legal guardian, if applicable, has the right to withdraw his/her consent at any 
time without prejudice. In the Informed Consent Form, it is stated that if consent is withdrawn, any data collected 
before withdrawal of consent will be kept. One original signed Informed Consent Form must be kept at the study 
site, and one is provided to the subject and/or subject’s parent or legal guardian, as applicable. 
For details, see the Subject Information Sheet and Informed Consent Form. 
7 
Safety Reporting 
7.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal product and 
which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, a new disease or 
worsening in severity or frequency of a concomitant disease, temporally associated with the use of a medicinal 
product, whether or not the event is considered causally related to the use of the product. 
Although abnormal laboratory values are typically not considered AEs, the following considerations may result 
in an abnormal laboratory value being considered an AE: 
• 
A laboratory test result that meets the criteria for an Serious Adverse Event (SAE) 
• 
A laboratory test result that requires the subject/patient to receive specific corrective therapy 
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• 
A laboratory abnormality that leads to discontinuation of therapy 
• 
A laboratory abnormality that the health care provider considers to be clinically significant 
Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death. Note that death is an outcome of an event. The event(s) causing death should be recorded. 
• 
In the view of the Health care provider, places the subject/patient at immediate risk of death (a life 
threatening event); however, this does not include an event that, had it occurred in a more severe form, 
might have caused death 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect 
• 
An SAE may also be any other medically important event that, in the opinion of the Health care provider, 
may jeopardize the subject/patient or may require intervention to prevent one of the other outcomes listed in 
the definition above.  (Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an inpatient 
hospitalization.) 
Adverse Drug Reactions  
An adverse drug reaction (ADR) is an AE for which there is at least a reasonable suspicion of a causal relationship 
between an AE and a suspected medicinal product. 
Product Quality Issues  
A Product Quality Issue (PQI) refers to defects related to the safety, identity, strength, quality, or purity of the 
product or with the physical characteristics, packaging, labeling, or design of the product. 
Special Situation Reports 
A Special Situation Report (SSR) includes any of the following events: 
• 
Pregnancy: Any case in which a pregnancy patient is exposed to a Takeda Product or in which a female 
patient or female partner of a male patient becomes pregnant following treatment with Takeda Product. 
Exposure is considered either through maternal exposure or via semen following paternal exposure. 
• 
Breastfeeding: Infant exposure from breast milk 
• 
Overdose: All information of any accidental or intentional overdose 
• 
Drug abuse, misuse or medication error: All information on medicinal product abuse, misuse or medication 
error (potential or actual) 
• 
Suspected transmission of an infectious agent: All information on a suspected (in the sense of confirmed or 
potential) transmission of an infectious agent by a medicinal product.  
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• 
Lack of efficacy of Takeda Product  
• 
Occupational exposure 
• 
Use outside the terms of the marketing authorization, also known as “off-label” 
• 
Use of falsified medicinal product 
A SSR should be reported even if there is no associated AE. 
Adverse Events not being collected 
Information on all adverse events should be collected and recorded from healthcare professionals or consumers 
in the course of the study unless the protocol provides with a due justification for not collecting certain adverse 
events. Any reference to adverse events that are not collected should be made using the appropriate level of the 
MedDRA classification. 
The healthcare professional or patient shall be informed of the possibility to report directly to the local Takeda 
Pharmacovigilance department or national pharmacovigilance reporting system any adverse reactions not being 
collected as part of the study. These will be treated as spontaneous reports and independent of the study. 
7.2 
Collection and Recording of Adverse Events, Special Situation Reports and Product 
Quality Issues 
Collection and recording of SAEs, AEs, ADRs SSRs and PQI will commence once the study participant has 
provided informed consent.  
• 
SAEs, AEs, ADRs, SSRs and PQIs in the healthcare record or other applicable source data that 
are part of the study objectives or endpoints 
Events/issues which are part of the study objectives or endpoints will be systematically identified 
and collected from healthcare records or other applicable source records and summarized as part 
of any interim analysis and in the final study report. Such events do not need to be notified as 
individual reports to Takeda Pharmacovigilance. 
• 
SAEs, AEs, SSRs and PQIs in the healthcare records or other applicable source data that are not 
part of the study objectives and endpoints 
Events/Issues which are not part of the study objectives and endpoints will not be abstracted or collected 
from healthcare records or other applicable source records. 
• 
SAEs, AEs, ADRs, SSRs and PQIs spontaneously reported to the investigator(s) or research team 
(not required for database studies) 
If during the conduct of the study the investigator(s) or a member of the research team is spontaneously informed 
by a healthcare professional or patient of an SAE, AE, ADR, SSR or PQI where the event/issue pertains to a Takeda 
product (or unbranded generic), such information should be forwarded to the relevant Takeda Pharmacovigilance 
department within 1 working day for fatal or life-threatening SAEs, within 4 calendar days for other SAEs, and 
within 7 calendar days for all other events. This includes events spontaneously notified to the investigator(s) or 
research team which are study endpoints and also events spontaneously notified which are not study endpoints. As 
such reports are spontaneously notified, causality of any adverse events should be assumed unless there is evidence 
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This is typically achieved by the investigator completing the adverse event report pages of an electric CRF or by 
submitting an AE Report Form to Takeda. 
The Investigator may be contacted by Takeda to obtain additional information on the event or for data clarification. 
The investigator shall make best effort to obtain the requested additional information and will notify Takeda within 
1 working day of obtaining the additional information for a fatal or life-threatening SAE, within 4 calendar days 
for other SAEs, and within 7 calendar days for all other events/issues. 
Takeda Contact Information 
Spontaneous reports are notified to the local Pharmacovigilance Department in Spain, through the email address 
farmacovigilancia@takeda.com for Legacy Takeda products and to the email address DrugSafety@Shire.com for 
Legacy Shire products. 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory Authorities 
- 
The expedited reporting of AEs and SSRs that are study endpoints to regulatory agencies is not required. 
Such events should be included in the Clinical Study Report. 
- 
For spontaneously reported events that are not study endpoints, the Sponsor shall notify regulatory 
agencies in accordance with local regulatory requirements or Sponsor’s post‐marketing commitments. 
8 
Data Quality Control and Assurance 
8.1 
Quality Control 
The data will be entered by the investigators themselves and/or authorized personnel directly in the electronic case 
report form (eCRF). A data management plan (DMP) will be created to describe the method and procedure for 
each data management step for the study, from electronic Case Report Form (eCRF) design up to final database 
delivery. 
Participating Investigators will be trained before start of data collection on: 
- 
the background and objectives of the study 
- 
study procedures 
- 
safety reporting 
- 
ethical regulations, 
- 
data entering and database in the eCRF 
The data quality will be assured by using the following methods of quality review: 
- remote monitoring contacts performed by the CRO for the verification of the compliance of the data presented 
in the CRF with the data of the primary documentation, signature of the Informed Consent - source data 
verification (SDV) if applicable 
- Once the data collection has been completed, the CRO will perform remote close out visits in all the participant 
sites. The close out visit will remotely confirm any potential remaining queries and review that study documents 
are in place. 
The eCRFs will include programmable edit checks to obtain immediate feedback if data are missing, out of range, 
illogical or potentially erroneous. The Edit Checks Specifications (Data Validation Plan (DVP)) is included in the 
eCRF specification documentation. These checks will be performed once data is entered into the eCRF. Thus the 
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data entered into the eCRF will be validated within the system and the physician will receive alerts for missing or 
inconsistent data. In case any changes of already entered data will be required, an audit trail will be available. 
The investigator(s)/institution(s) will allow study-related monitoring, audits, independent ethics committee/- 
review board (IEC/IRB) review, and regulatory inspection(s), providing direct access to source data documents. 
8.2 
Audit from Quality Assurance Unit 
The Quality Assurance (QA) unit may audit the study to ensure that study procedures comply with the protocol 
and standard operating procedures, and that collected data is correct and complete. 
8.3 
Inspection by IRB/IEC or Competent Authority 
Representatives from IRB/IEC or Competent Authority may in rare cases wish to inspect the study on site. Upon 
receiving notification of such inspection, the Study Site Responsible must immediately contact the Sponsor and 
must make the records available as requested. The Inspector must be reminded up front that consent to access to 
personal data has not been obtained from the participants in this study. 
8.4 
Data Management 
This study will be performed by the CRO IQVIA with guidance, input, review and approval of Takeda, including 
development of materials, recruitment, training and management of sites, electronic data capture and data 
management and analysis.   
Data Management will be carried out according to a Data Management Plan (DMP), which must be written and 
approved before the design of the study database is finalised. The data management provider should approve all 
data formats before the data collection tools are made available to the sites. 
If the written informed consent of a subject is known not to be available in spite of it being required, data for this 
subject is not entered into or is deleted from the database. If a subject is erroneously included in the study more 
than once only the data relating to the first inclusion will be kept in the database and be available for analysis. 
Data from later inclusions will be transferred to the first dataset when relevant, i.e. if collected within the time 
frame of the first follow-up period.  
The current Standard Coding Instructions for coding of medical history, concomitant illness (MedDRA), 
concomitant medication (WHO-Drug) and adverse events/reactions (MedDRA) must be followed. 
Centres will be selected by sponsor and that will also be part of data analysis. Each investigator will nominate a 
study investigator for the centre that will collect the study data. 
The Study Site will receive data collection tools (CRFs, access to electronic data capture, etc.) from the CRO. 
Whenever possible, complete data sets should be entered. Text field entries and any data collected on paper should 
be legible and follow the CRF completion guide.  
Patients’ data will be collected from the source documents for each patient in the study, consisting of medical 
records containing demographic data, medical, treatment and diagnostic documentation and laboratory 
assessments, from the medical charts.  
All data will be collected and entered directly into the electronic case report form (eCRF) designed for this study. 
All participating sites will have access to the data entered regarding the individual site its own enrolled patients. 
All sites will be fully trained on using the on-line data capture system, including eCRF completion guidelines and 
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help files. Sites will be responsible for entering extracted patient data into a secure internet-based platform via the 
eCRF.  Investigators and site personnel will be able to access their account with a username and password. All 
eCRFs should be completed by designated, trained personnel or the study coordinator, as appropriate. In most 
cases, the eCRF should be reviewed, electronically signed, and dated by the Principal investigator. All changes or 
corrections to eCRFs are documented in an audit trail and an adequate explanation is required.  
8.4.1 
Data Collection Tools and Flow 
Data entered manually will be collected via electronic case report form (eCRF). Technical support will be provided 
for all study participants throughout the study. The investigator will be responsible for completion of all the 
sections of the eCRF and that the entries correspond to his or her professional experience and regular clinical 
practice. The CRO will be responsible for supervising recruitment in this study through the eCRFs. In the data 
collection period, standard monthly emails will be sent to the sites during data extraction, to inform about 
progression, tackle any problems and remind the investigators of their responsibilities in the study. 
PRO data will be collected on paper format and the data from the questionnaires will be entered into the eCRF 
system by the investigator team. Takeda will perform oversight of the data management of this study, including 
approval of the CRO data management plans and guidance. The CRO will produce eCRF specifications for the 
study based on the study initiator’s templates including quality checking to be performed on the data. 
In all cases, the doctor must keep the original documents of each study patient. All the information entered in the 
eCRF must be traceable to the original documents in the patient's file. Only the study site doctors will keep a 
patient follow-up sheet, with a list of the patient numbers together with names and dates of birth, to enable their 
identification. The doctor must also keep the original informed consent form signed by the patient (the patient 
will be given a signed copy), if required. 
The Study Site Responsible must sign off the complete data set for each subject, confirming the collected data. 
ADR data reported according to section 7 and data on serious AE/ADR reactions collected according to section 4 
should be signed off separately by a physician who may or may not be involved in the study.  
9 
Statistical Methods and Determination of Sample Size 
9.1 
Statistical Analysis Plan 
This study is observational and epidemiological methods will be employed for data analyses. 
Statistical analyses will be performed by IQVIA Information S.A. with SAS® statistical software version 7.15 or 
higher or R. A Statistical Analysis Plan (SAP) with a detailed description of analyses to be performed and 
imputation methods to deal with missing data and censoring will be developed. The final SAP will include (mock) 
table shells to be populated for the clinical study report (CSR). The SAP will be prepared and accepted before the 
data analysis initiation. The SAP describes the statistical analyses as foreseen at the time of planning the study. 
Any known deviations from the planned analyses, the reason for such deviations and all alternative / additional 
statistical analyses that may be performed as well as the final statistical analysis must be described in a revised 
SAP before completion of data collection. All later deviations and / or alterations will be summarised in the 
Clinical Study Report. 
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In this non-interventional study, retrospective data from medical charts and data at the study visit will be collected 
for patients with narcolepsy. Once the study has been completed and all data from the last patient have been 
recorded, the database will be closed, and statistical analysis will be performed. 
For details of the statistical analyses please refer to the Statistical Analysis Plan. 
9.2 
General considerations 
A description of all patients included in the study will be performed. All patients participating in the study who 
meet the eligibility criteria will be included in the study population. Continuous variables will be described by the 
number of patients with valid/missing observations, mean, standard deviation (SD), median, 25 and 75 percentiles 
(P25 and P75, respectively), minimum and maximum. Categorical variables will be described by frequencies and 
related percentages. A p-value lower than 0.05 will be considered significant. Count variables (healthcare 
utilization) will be analysed as unadjusted rates.  
Questionnaire scores provided by patients will be described using the descriptive measures described above, and 
according to the manual users of each questionnaire. 
Descriptive analysis will be performed of all collected data except data collected only for the purpose of data 
cleaning, i.e. all data listed in section 4. 
Descriptive analyses will be conducted to describe the sociodemographic and health characteristics of the total 
sample and the narcolepsy and sub study groups. Bivariate analyses (chi-square tests for categorical variables and 
t-tests for continuous variables) will be conducted to assess whether patients with narcolepsy diagnosis with or 
without cataplexy differed significantly on any sociodemographic or health characteristic variables. Finally, 
percentage of patients with cataplexy will be presented.  
9.2.1 
Evaluable patients 
All patients fulfilling all inclusion and none of exclusion criteria, giving their informed consent and completing 
main eCRF data will be considered as evaluable patients.  
9.2.2 
Primary Endpoint   
• 
Describe treatment patterns in narcolepsy patients in Spain.The following subgroups will be analyzed: 
o 
Total narcolepsy population 
 
Patients with and without cataplexy (Type 1 and Type 2) 
 
Narcolepsy patients Type 1 and Type 2 previously treated and naïve-treatment patients 
The percentage of use of treatments (yes / no) and the use of different treatments (pharmacological and non-
pharmacological) in the study visit will be described in global and stratified by the different subgroups describe 
above: type of narcolepsy and if previously treated.  Also, a description of percentage of use of each type of 
treatment in the study visit will be stratified by type of hospital (public or private centers).  
9.2.3 
Secondary Endpoint(s) 
• 
Describe sociodemographic and clinical characteristics of patients with narcolepsy (both treated and 
untreated patients)  
Sociodemographic and clinical characteristics (general clinical history and narcolepsy characteristics) of 
patients with narcolepsy collected in the study visit will be presented stratified by the use of treatments in 
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the study visit (untreated or treated patients). Comparisons between groups will be performed using a Chi-
Square test for categorical variables and t-test or non-parametric test for continuous variables.  
• 
To describe specialists involved in diagnosis of patients with narcolepsy 
The percentage of different specialists who diagnosed narcolepsy will be presented  
• 
To describe outcome measures used in real-world as described in patients’ medical records 
The percentage of the different procedures or tests for the diagnosis of narcolepsy will be described: ESS, 
PSG, MSLT, absence/presence of cataplexy, number of cataplexy attacks, number of sleep-onset REM 
periods (SOREMPs), absence/presence of apneas and /or Apnea-hypopnea index (AHI), hypocretin levels 
etc, used for narcolepsy diagnosis will be described. 
Time since first symptoms to diagnosis and time from diagnosis to first treatment will be described, also the 
percentage of patients who had each type of procedure performed at diagnosis (ESS, PSG, MSLT, PSG, 
other).  
• 
To evaluate and describe clinician assessments (effectiveness) of the  used narcolepsy treatments in the study 
period since diagnosis: 
o 
Percentage of pharmacological treatments and interventions received in relation with the presence 
of most typical symptoms will be presented: excessive daytime sleepiness, cataplexy, sleep paralysis, 
and hallucinations. Symptomatology will be stratified by current treatment used for narcolepsy.  
o 
Percentage of pharmacological treatments at each line 
o 
Percentage of patients in which information on scales used to measure treatment outcomes is 
available: ESS , MWT and SART at the study visit will be described and the relation with the 
treatment received. 
o 
A description of  non-pharmacological treatments: Take short naps; Maintain a regular sleep 
schedule; Avoid caffeine or alcohol before bed; Avoid smoking, especially at night; Exercise daily; 
Avoid large, heavy meals right before bedtime; Relax before bed 
• 
To estimate direct and indirect healthcare resources utilization  use by narcolepsy patients in Spain, based 
on measures of healthcare resource utilization, and on reported work productivity loss in terms: 
o 
Direct medical healthcare resources used by patients with narcolepsy will be described in terms of 
percentage of patients who used each direct healthcare resource in the las 12 months including 
previous treatments for narcolepsy, outpatient visits, clinical tests, emergency room/department 
visits, hospitalizations and complication associated to narcolepsy . Also, it will be described the 
number of each type of direct resources used by patient/year (assuming as zero when patients did 
not used it). To compute total cost, the following direct cost components will be summed for fees 
for visits to doctors, laboratory tests and imaging tests, outpatient visits, emergency room visits, 
inpatient stays, rehabilitation stays, and drug treatments related to MS. Unitary costs for health care 
resources will be retrieved from different databases.  
o 
Indirect health resources in the last 7 days will be described through the WPAI questionnaire scores 
obtained for: 
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1.  Absenteeism (work time missed). 
2.  Presenteeism (impairment at work / reduced on-the-job effectiveness) 
3.  Work productivity loss (overall work impairment / absenteeism plus presenteeism) 
4.  Activity Impairment / disability . 
o 
Indirect health care due to occupational accidents  motor vehicle accidents (MVAs) and near miss 
accidents (NMAs) will also be described, through the answer of the two following questions: Have 
you had a motor vehicle accident at work during the last years?”, “Have you had a near-miss driving 
accident during the last year? 
o 
Costs will be calculated considering the healthcare resource use and will be described in the final 
report. Unitary costs for direct resources will be obtained from E-SALUD database 
(http://esalud.oblikue.com/). If necessary, costs will be updated using Consumer Price Index 
published by INE. And unitary costs for treatments for narcolepsy will be obtained from BOTPLUS– 
Consejo General de Colegios Oficiales de Farmacéuticos (https://botplusweb.portalfarma.com/), 
considering active drug, posology and duration of the prescription. Costs will be reported at annual 
basis and calculated at patient-level according to the resources used obtaining the following cost 
drivers for descriptive purposes:   
 
Annual cost of treatment received 
 
Annual cost of routine monitoring visits (specialists and GPs) 
 
Annual cost of conducted tests 
 
Annual cost of emergency rooms visits  
 
Annual cost of hospitalizations  
 
Annual cost of complications derived from narcolepsy 
• 
To describe the Health-Related Quality of Life (HRQoL) of patients with narcolepsy in Spain: 
o 
The EQ-5D scores of patients with narcolepsy in Spain will be described according to the following 
dimensions 
 
Mobility 
 
Self-Care 
 
Usual activities 
 
Pain / Discomfort 
 
Anxiety / Depression 
• 
To describe treatment satisfaction of patients with narcolepsy in Spain  
o 
TSQM-9 domains will be described, including convenience, effectiveness and global satisfaction.  
• 
To describe  burden of illness in terms of associated comorbidities and associated disorders 
o 
Percentages (%) of most prevalent comorbidities and other concomitant disorders associated with 
narcolepsy will be described. 
o 
Charlson Comorbidity Index(25) (CCI), score is a method to estimate 10-year mortality based on a 
score from a range of 12 comorbidities, the comorbidity score ranges from 0 to a maximum of 24 
points. 
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• 
To describe adverse reaction associated to narcolepsy treatments 
o 
Describe type of adverse events reported   
9.2.4 
Exploratory Endpoint(s)  
• 
Identify the proportion of patients with narcolepsy (with and without cataplexy) diagnosed and managed in 
public hospitals in Spain 
o 
The percentage of total number of patients with narcolepsy attended in the participating site 
according to routine clinical practice with at least 12-months follow up after over total population 
under the hospital’s circumscription 
o 
New patients diagnosed with narcolepsy in the last year in the participating sites 
• 
Evaluate and describe the diagnosis and treatment management of patients with narcolepsy up to one year 
before diagnosis (if this information is not available in the medical charts, this objective will be assessed 
through a patient survey). 
o Description (%) treatments received for narcolepsy in the last year will be described. 
• 
Describe utilization of health care resources associated with narcolepsy patients in Spain, before and after 
diagnosis of narcolepsy 
o 
Description (quantity and type) of healthcare resources associated with narcolepsy patients before 
and after being diagnosed for this condition.  
• 
Describe utilization of health care resources associated with narcolepsy patients in Spain, before and after 
treatment for narcolepsy 
o 
In those patients that received treatment within the 1st year after diagnosis of narcolepsy: Description 
(quantity and type) of healthcare resources associated with narcolepsy patients before and after 
receiving treatment for this condition 
ADRs reported in the study as well as ADRs reported directly to authorities and to Takeda International Drug 
Safety according to Section 7 and not captured in the study database will be extracted from the overall safety 
database and the study database and listed or tabulated in the final report in the standard way of presenting such 
data in a Periodic Safety Update Report (PSUR). 
9.3 Interim Analyses 
No interim analyses are planned for this study.  
9.4 
Determination of Sample Size 
The main objective of this study is to describe treatment patterns of narcolepsy patients in Spain.  
Since it is an exploratory analysis, the sample size (N) will be calculated based on statistical criteria, using the 
criterion of maximum indetermination, when the percentage is expected to be around 50%.  
A sample of 196 evaluable patients is sufficient to estimate a population percentage of 50%, with a 95% 
confidence interval of ± 7 percentage units. In this way, the continuous variables will be estimated with an 
accuracy of 0.14 standard deviations (SD).  
Taking into account that around 20% of patients will not have any evaluable data or will be not considered 
evaluable for the study purposes, the number of patients with narcolepsy to be included will be approximately 
245 patients: 172 patients with type 1 narcolepsy and 73 patients with type 2 narcolepsy (a relation of 70%-30%). 
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10 Reports 
The Final Study Report should be available within one year from collection of the last data point, and the 
participating sites should be informed about the results when the report is finalised. 
11 Publication, Disclosure, and Clinical Trial Registration Policy 
The Sponsor aims to have the results of this study published. 
The Sponsor has the right to use the data and results for regulatory purposes and for internal presentation within 
the company and to partners. 
Takeda may post the results of the study on ClinicalTrials.gov and/or other publicly accessible websites, as 
required by Takeda Policy/Standard, applicable laws and/or regulations. 
12 Archiving of Study Documentation 
During the course of the study the Site Responsible must as a minimum file the below essential documents in the 
Study Site File: 
• 
Written agreement between the Sponsor and the participating site. 
• 
The study protocol and any amendments 
• 
Signed and dated protocol agreement and amendment agreements, if any, with the original signature of the 
Site Responsible 
• 
Subject Information Sheet and Informed Consent Form in local language (notified to / approved by 
Independent Ethics Committees (IECs) / Institutional Review Boards (IRBs) as locally required), including 
the original signed Forms 
• 
The list of participating subjects 
• 
Written IEC / IRB approval / vote according to local regulations 
• 
Authority approval according to local regulations 
• 
The completed CRFs 
• 
The progress reports 
After final database lock the Site Responsible must as a minimum store the list of participating subjects and the 
signed Informed Consent Forms on site for 5 years. The Site Responsible should store additional study 
documentation for a longer period of time as required by any local regulations and/or hospital requirement.  
 
 
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13 References 
 
1. 
Sarkanen T, Alakuijala A, Partinen M. Ullanlinna Narcolepsy Scale in diagnosis of narcolepsy. Sleep. 
2019;42(3):zsy238. 
2. 
Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy symptomatology and 
diagnosis in the European general population. Neurology. 2002;58(12):1826-33. 
3. 
Ohayon M, Priest R, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy symptomatology and 
diagnosis in the European general population. Neurology. 2002;58(12):1826-33. 
4. 
Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of 
narcolepsy. Sleep medicine. 2004;5(1):37-41. 
5. 
Frauscher B, Ehrmann L, Mitterling T, Gabelia D, Gschliesser V, Brandauer E, et al. Delayed diagnosis, 
range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of 
the innsbruck narcolepsy cohort. Journal of clinical sleep medicine : JCSM : official publication of the American 
Academy of Sleep Medicine. 2013;9(8):805-12. 
6. 
Kornum BR, Knudsen S, Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, et al. Narcolepsy. Nature reviews 
Disease primers. 2017;3:16100. 
7. 
Dunne L, Patel P, Maschauer EL, Morrison I, Riha RL. Misdiagnosis of narcolepsy. Sleep & breathing 
= Schlaf & Atmung. 2016;20(4):1277-84. 
8. 
Barateau L, Dauvilliers Y. Recent advances in treatment for narcolepsy. Therapeutic advances in 
neurological disorders. 2019;12:1756286419875622. 
9. 
de Biase S, Nilo A, Gigli GL, Valente M. Investigational therapies for the treatment of narcolepsy. Expert 
opinion on investigational drugs. 2017;26(8):953-63. 
10. 
Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet (London, England). 
2007;369(9560):499-511. 
11. 
Bhattarai J, Sumerall S. Current and Future Treatment Options for Narcolepsy: A Review. Sleep science 
(Sao Paulo, Brazil). 2017;10(1):19-27. 
12. 
Cohen A, Mandrekar J, Louis EKS, Silber MH, Kotagal S. Comorbidities in a community sample of 
narcolepsy. Sleep medicine. 2018;43:14-8. 
13. 
Thorpy MJ, Hiller G. The Medical and Economic Burden of Narcolepsy: Implications for Managed Care. 
American health & drug benefits. 2017;10(5):233-41. 
14. 
Emsellem HA, Thorpy MJ, Lammers GJ, Shapiro CM, Mayer G, Plazzi G, et al. Measures of functional 
outcomes, work productivity, and quality of life from a randomized, phase 3 study of solriamfetol in participants 
with narcolepsy. Sleep medicine. 2020;67:128-36. 
15. 
Kok SW, Overeem S, Visscher TL, Lammers GJ, Seidell JC, Pijl H, et al. Hypocretin deficiency in 
narcoleptic humans is associated with abdominal obesity. Obesity research. 2003;11(9):1147-54. 
16. 
Dauvilliers Y, Jaussent I, Krams B, Scholz S, Lado S, Levy P, et al. Non-dipping blood pressure profile 
in narcolepsy with cataplexy. PloS one. 2012;7(6):e38977. 
17. 
Plazzi G, Ferri R, Antelmi E, Bayard S, Franceschini C, Cosentino FI, et al. Restless legs syndrome is 
frequent in narcolepsy with cataplexy patients. Sleep. 2010;33(5):689-94. 
18. 
Jennum P, Ibsen R, Petersen ER, Knudsen S, Kjellberg J. Health, social, and economic consequences of 
narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. Sleep medicine. 
2012;13(8):1086-93. 
19. 
Flores NM, Villa KF, Black J, Chervin RD, Witt EA. The Humanistic and Economic Burden of 
Narcolepsy. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep 
Medicine. 2016;12(3):401-7. 
20. 
Daniels E, King MA, Smith IE, Shneerson JM. Health-related quality of life in narcolepsy. Journal of 
sleep research. 2001;10(1):75-81. 
21. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity 
impairment instrument. Pharmacoeconomics. 1993;4(5):353-65. 
22. 
Herdman, M., Gudex, C., Lloyd, A. et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res 20, 1727–1736 (2011). https://doi.org/10.1007/s11136-011-9903-
x 
23. 
Molina Y, Choi SW, Cella D, Rao D. The stigma scale for chronic illnesses 8-item version (SSCI-8): 
development, validation and use across neurological conditions. International journal of behavioral medicine. 
2013;20(3):450-60. 
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24. 
Sweileh WM, Ihbesheh MS, Jarar IS, Taha ASA, Sawalha AF, Sa'ed HZ, et al. Self-reported medication 
adherence and treatment satisfaction in patients with epilepsy. Epilepsy & Behavior. 2011;21(3):301-5. 
25. 
Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson 
comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. 
American journal of epidemiology. 2011;173(6):676-82. 
 
 
 
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14 APPENDICES 
 
 
 
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Appendix 1: Case Report Form 
 
 
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Appendix 2: Study Investigator Agreement 
 
 
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Appendix 3: Ethics Committee Approval 
 
 
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Appendix 4: Patient Information Sheet  
 
 
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Appendix 5: Informed Consent Form 
 
 
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Appendix 6: Economic Details 
 
 
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Appendix 7: Productivity loss, Absenteeism, Presenteeism, Disability (WPAI 
questionnaire). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 8: EQ-5D questionnaire. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 9: Stigma Scale chronic illnesses (SSCI-8)  
 
 
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Appendix 10:  Treatment Satisfaction Questionnaire for Medication (TSQM-9) 
 
Extracted from Supplemental materials for: Palumbo A, Bringhen S, Mateos MV, Larocca A, 
Facon T, Kumar SK, et al. Geriatric assessment predicts survival and toxicities in elderly 
myeloma patients: An International Myeloma Working Group report. Blood. 2015;2068–74. 
 
 
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Appendix 11: Takeda AE Report Form 
 
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