Quality of Life Measurement Using Wrist Actigraphy in HCV Genotype 1 Infected, Treatment naïve Patients Suffering From Fatigue and Receiving Ombitasvir, Paritaprevir, and Ritonavir Tablets and Dasabuvir Tablets (Viekirax®/Exviera®; 3D Regimen): The HEMATITE Study
Conditions: Chronic Hepatitis C Virus (HCV)
Sponsor: AbbVie

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AbbVie AG (AbbVie) 
Post Marketing Observational Study  
Protocol P16-272 
Quality of Life measurement using wrist 
actigraphy in HCV genotype 1 infected, 
treatment naïve patients suffering from 
fatigue and receiving ombitasvir, paritaprevir, and 
ritonavir tablets and dasabuvir tablets 
(Viekirax®/Exviera®; 3D regimen):
The HEMATITE Study 
ProductName:
ombitasvir,paritaprevir,andritonavirtabletsand
dasabuvirtablets(Viekirax®/Exviera®;3Dregimen)
TypeofStudy:
ObservationalStudy
StatusofDocument:
V1.0
Date:
20September2016
Sponsor
AbbVieAG,Switzerland
This study will be conducted in compliance with this protocol.  
Confidential Information. No use or disclosure outside AbbVie is permitted without prior written
/$5

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Title 
Quality of life measurement using wrist actigraphy in HCV 
genotype 1 infected, treatment naïve patients suffering from 
fatigue and receiving ombitasvir, paritaprevir, and ritonavir tablets 
and dasabuvir tablets (Viekirax®/Exviera®; 3D regimen): The 
HEMATITE Study  
Protocol Version Identifier 
P16-272 
Date of Last Version of 
Protocol 
20 September 2016 
EU PAS Register Number 
Not Applicable 
Active Substance 
Ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets 
(Viekirax®/Exviera®,, 3D regimen) 
Medicinal Product 
Ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets 
(Viekirax®/Exviera®,, 3D regimen)  
Product Reference 
Not Applicable 
Procedure Number 
Not Applicable 
Marketing Authorization 
Holder(s) 
AbbVie AG Schweiz 
Neuhofstrasse 23 
CH - 6341 Baar 
Joint PASS 
Not Applicable 
Research Question and 
Objectives 
To observe the impact of the 3D regimen on total daytime physical 
activity in Hepatitis C Virus (HCV) positive patients in a real-world 
setting. 
Objectives: 
x 
To observe changes in physical activity (assessed by 
means of an electronic wrist-worn activity tracker) in 
patients with newly initiated 3D regimen before, during 
and after treatment, 
x 
To correlate subjective fatigue (assessed by means of the 
validated FSS (Fatigue Severity Scale) questionnaire) and 
physical activity, 
x 
To observe the proportion of patients achieving sustained 
virologic response 12 weeks after end of treatment with 
3D (SVR12).  

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Country(-ies) of Study 
Switzerland 
Authors 
AbbVie AG Schweiz 
 
Marketing Authorization Holder(s) 
Marketing Authorization Holder(s) 
AbbVie AG Schweiz 
Neuhofstrasse 23 
CH - 6341 Baar 
MAH Contact Person 
Not applicable 
 
 
 

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1.0 
Table of Contents 
1.0 
Table of Contents ................................................................................................. 4 
2.0 
Abbreviations ........................................................................................................ 6 
3.0 
Responsible Parties ............................................................................................. 7 
4.0 
Abstract ................................................................................................................ 8 
5.0 
Amendments and Updates ................................................................................. 13 
6.0 
Milestones .......................................................................................................... 13 
7.0 
Background and Rationale ................................................................................. 13 
8.0 
Research Question and Objectives .................................................................... 15 
8.1 
Research Question ............................................................................................. 15 
8.2 
Objectives ........................................................................................................... 15 
8.2.1 
Primary Objective ............................................................................................... 15 
8.2.2 
Secondary Objectives ........................................................................................ 15 
9.0 
Research Methods ............................................................................................. 15 
9.1 
Study Design ...................................................................................................... 15 
9.1.1 
Description of Activities ...................................................................................... 17 
9.1.2 
Description of Visits ............................................................................................ 20 
9.1.3 
Product Supply ................................................................................................... 21 
9.1.4 
Termination Criteria ............................................................................................ 21 
9.2 
Setting ................................................................................................................ 22 
9.2.1 
Target Population ............................................................................................... 22 
9.2.2 
Study Duration .................................................................................................... 23 
9.2.3 
Investigator Selection Criteria ............................................................................ 23 
9.3 
Variables ............................................................................................................. 23 
9.3.1 
Primary Variable ................................................................................................. 23 
9.3.2 
Secondary Variables .......................................................................................... 24 
9.4 
Data Sources ...................................................................................................... 24 
9.5 
Study Size .......................................................................................................... 24 
9.6 
Data Management .............................................................................................. 25 
9.7 
Data Analysis ...................................................................................................... 25 
9.8 
Quality Control .................................................................................................... 26 

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9.9 
Limitations of the Research Methods ................................................................. 27 
9.10 
Other Aspects ..................................................................................................... 28 
10.0 
Protection of Human Subjects ............................................................................ 28 
11.0 
Management and Reporting of Complaints ........................................................ 28 
11.1 
Medical Complaints ............................................................................................ 29 
11.1.1 
Adverse Event Definition and Serious Adverse Event Categories ..................... 29 
11.1.2 
Severity ............................................................................................................... 31 
11.1.3 
Relationship to Pharmaceutical Product ............................................................ 31 
11.1.4 
Serious-, non Serious Adverse Event and Pregnancy Collection Period ........... 32 
11.1.5 
Adverse Event reporting ..................................................................................... 32 
11.1.6 
Serious Adverse Event Reporting ...................................................................... 32 
11.1.7 
Pregnancy Reporting .......................................................................................... 33 
11.2 
Product Complaint .............................................................................................. 33 
11.2.1 
Definition ............................................................................................................. 33 
11.2.2 
Reporting ............................................................................................................ 34 
12.0 
Plans for Disseminating and Communicating Study Results ............................. 34 
13.0 
References ......................................................................................................... 36 
Annex 1. 
ActiGraph GT9X Link [26] .................................................................................. 39 
Annex 2. 
Fatigue Severity Scale (FSS) [38] ...................................................................... 41 
Annex 3. 
ICD-10 Version:2016 [41] ................................................................................... 42 
Annex 4. 
List of Protocol Signatories ................................................................................. 43 
Annex 5. 
Requirements for non-interventional studies per local laws and 
regulations .......................................................................................................... 44 

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2.0 
Abbreviations 
3D regimen 
Ombitasvir, Paritaprevir, and Ritonavir tablets (Viekirax®); Dasabuvir tablets 
(Exviera®) 
AASLD 
American Association for the Study of Liver Diseases 
AE 
Adverse Event 
BMI 
Body Mass Index 
CA 
Competent Authorities 
CHCV 
Chronic Hepatitis C infection, defined as the presence of detectable viral 
replication for at least six months. 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
FSS 
Fatigue Severity Scale 
HCV 
Hepatitis C Virus 
ICMJE 
International Committee of Medical Editors 
LSLV 
Last Subject Last Visit 
MAH 
Marketing Authorization Holder 
PMOS 
Post Marketing Observational Study 
QoL 
Quality of Life 
RBV 
Ribavirin 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SAP 
SmPC 
Statistical Analysis Plan 
Summary of Product Characteristics 
SVR 
Sustained Virologic Response 
SVR12 
Sustained Virologic Response at12 weeks after EOT 
V 
Visit 
WHO 
World Health Organization 

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3.0 
Responsible Parties 
Study Designated Physician (SDP): 
Protocol Authors: 
Pharmacovigilance AbbVie AG Schweiz:  
Quality Assurance AbbVie AG Schweiz:  
Vendor:
Contact details and a list of investigators will be kept at AbbVie and will be available upon request. 

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4.0 
 Abstract 
Title: Quality of life measurement using wrist actigraphy in HCV genotype 1 infected, treatment 
naïve patients suffering from fatigue and receiving ombitasvir, paritaprevir, and ritonavir tablets 
and dasabuvir tablets (Viekirax®/Exviera®; 3D regimen): The HEMATITE Study 
Background and Rationale: 
Physical and mental fatigue is the most common symptom reported by patients with Hepatitis 
C Virus (HCV), which highly impacts their overall quality of life. AASLD (American Association 
for the Study of Liver Diseases ) and EASL (European Association for the Study of the Liver) 
guidelines therefore rate the treatment of HCV patients suffering from debilitating fatigue as a 
high priority. This cardinal symptom presents regardless of the stage of liver fibrosis and is 
difficult to quantify objectively. Similar to other potential reasons for physical fatigue, such as 
hepatic encephalopathy, increasing evidence suggests a direct viral impact on the central 
nervous system (CNS). Data demonstrating a longitudinal change of debilitating physical 
fatigue and increased daytime physical activity upon treatment with 3D regimen are missing to 
date and are anticipated by the Swiss scientific HCV community [1, 2]. 
The rationale for this observational study is to observe the impact of therapy with 3D regimen 
on physical activity of HCV patients suffering from debilitating fatigue. Furthermore, this study 
supports the Swiss Hepatitis Strategy, which seeks for the elimination of viral hepatitis in 
Switzerland within the next 15 years by creating awareness for patients with extrahepatic 
manifestations [3]. 
Research Question and Objectives:  
Does successful treatment with 3D regimen increase total daytime physical activity and reduce 
fatigue in HCV-positive patients? 
Primary objective: 
• 
To observe changes in physical activity in patients with newly initiated therapy with 3D 
regimen between pre-treatment (baseline) and post-treatment week 12 

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Secondary objectives: 
• 
To correlate subjective fatigue (assessed by means of Fatigue Severity Scale [FSS]) and 
physical activity (measured with an electronic activity tracker) at baseline, during and after 12 
weeks of treatment with 3D regimen  
• 
To observe the proportion of patients achieving sustained virologic response (SVR12) after 
treatment with 3D regimen (defined as HCV not detectable, 12 weeks after the last dose of 3D 
regimen) 
• 
To observe sleep efficiency (assessed by means of activity tracker) at baseline, during and 
after 12 weeks of treatment with 3D regimen  
Study Design:  
This is an observational, prospective, open label, single-arm, multi-centric, real-life study in 
HCV-positive patients (genotype 1).  
The study consists of a treatment preparation phase of 4 weeks to obtain baseline physical 
activity by use of a wrist-worn activity tracker, a treatment phase (12 weeks) and a follow-up 
phase (12 weeks) to evaluate treatment response. The activity tracker is worn for 4 weeks 
before each visit, to obtain stable individual activity data. At every visit, questionnaire-based 
fatigue is recorded (FSS questionnaire), according to routine clinical care.  

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Population:  
Patients are eligible for observation in this study, if the following applies:  
 
Inclusion Criteria: 
x 
Male and female patients aged ≥ 18 years  
x 
Treatment-naïve patients 
x 
Patients monoinfected with CHCV, GT1 (confirmed within the last 36 months or at 
physicians discretion in case of risk factors) 
x 
Non-cirrhotic patients (based on liver biopsy, fibroscan ≤ 9.6kPa and/or clinical signs) 
x 
The decision to treat with 3D regimen is made by the physician in accordance with the 
local Swiss product label prior to any decision to approach the patient to participate in 
this study. [4]  
x 
Patients with debilitating fatigue (FSS ≥ 4) 
x 
Patients willing to participate in the study, and willing to wear an activity tracker 
Exclusion Criteria:  
x 
Patients with sources of fatigue other than HCV (especially, severe depression (Annex 
4), cancer and hormonal disorders causing clinically significant fatigue)  
x 
Patients with conditions that do not allow to adhere to protocol and use of the device at 
investigator's discretion 
x 
Patients being wheelchair dependent  

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Variables:  
Primary Variable 
• 
Change of mean daytime physical activity between baseline (before treatment start) 
and post-treatment week 12 
Secondary Variables 
• 
Change of Fatigue Severity Score (FSS) between baseline, during and after 12 weeks 
of treatment with 3D regimen  
• 
Correlation between mean daytime physical activity and FSS at baseline, during and 
after 12 weeks of treatment with 3D regimen  
• 
Proportion of patients achieving SVR12 after treatment with 3D regimen (defined as 
HCV RNA not detectable 12 weeks after the last actual dose of 3D regimen)  
• 
Sleep efficiency at baseline, during and after 12 weeks of treatment with 3D regimen  
Data Sources:  
Source documents are defined as original documents. The investigator will document patient 
data, including FSS, in his/her own patient files which will serve as source data for the study. 
Physical activity and sleep data will be collected by use of wrist-worn activity trackers 
(ActiGraph GT9X Link) which will be processed by device-specific software (ActiLife 6) to 
obtain the activity and sleep-related variables for analysis (Annex 1).  All data collected by the 
activity tracker will be analyzed by the biostatistician at the end of the study. The data will not 
be seen by the investigators and patients at any time during data collection (between visit 1 
and visit 5 (Figure 1: Study Activities). 
Study Size:  
Approximately 100 patients in Switzerland will be enrolled.  
Data Analysis:  
All data will be analyzed by descriptive statistical methods. The correlation between physical 

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activity (assessed by the activity tracker) and the fatigue score (assessed by FSS) by visit, and 
the changes between baseline and the respective follow-up visits will be investigated by 
Spearman's rank correlation coefficient, supported by subgroup analyses. Two-sided 95% 
confidence intervals will be provided for primary and secondary endpoints, if applicable. 
Details of planned analyses will be described in a separate statistical analysis plan (SAP). 
Milestones:  
Start of Data Collection: 01 January 2017 
Last Patient first Visit: 31 December 2017 
Final Report of Study Results: 30 June 2019 

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5.0 
Amendments and Updates 
None 
6.0 
Milestones 
Major study milestones and their planned dates are as follows: 
Start of Data Collection: 
01 January 2017 
Last Patient first Visit   
31 December 2017 
Final Report of Study Results: 
30 June 2019 
 
7.0 
Background and Rationale 
Background 
Hepatitis C virus (HCV) infection is one of the most common liver diseases worldwide. 
Approximately 2% of the global population suffer from chronic HCV infection. In the majority of 
cases, HCV infection leads to chronic hepatitis [5]. While several genotypes of HCV exist, 
genotype 1 is the most common genotype in Europe, comprising the majority of infections [6]. 
HCV replicates as well within extrahepatic tissues and causes a wide range of extrahepatic 
manifestations. In fact, 40-74% of patients infected with HCV develop at least one extrahepatic 
manifestation during the course of their disease [7]. Over the recent years, studies have 
demonstrated that HCV infection can directly cause cognitive impairment, even in the absence of 
liver cirrhosis [8, 9]: The biological effect of HCV on the brain may result from viral penetration of 
the central nervous system (CNS) and/or central neuroinflammation leading to alterations in 
cerebral metabolism, immune activation, and neurotransmission [10, 11]. 
There are several potential reasons for the high prevalence of neuropsychological disorders in 
patients with HCV: Individuals with a pre-existing mental illness have been hypothesized to be 
more likely to contract HCV, or to abuse psychoactive substances affecting cognitive performance 
[12, 13]. Another predisposing factor may be pharmaceutical HCV treatment, which can trigger 
neuropsychological disorders [14]. However, an increasing body of evidence suggests a direct 

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biological effect of HCV infection resulting in brain dysfunction, which may improve following 
eradication of the virus [10, 11]. Finally, the hepatic function impairment (cirrhosis) may lead to 
minimal or overt encephalopathies with a broad range of neuropsychological symptoms [15].  
Clinically, HCV infection is strongly associated with multiple psychiatric comorbidities. Fatigue, i.e. 
sensations of both mental and physical exhaustion [16], is the most common symptom reported by 
patients with HCV [17, 18], which paradoxically may occur as well in conjunction with sleep 
disturbances, such as insomnia [19]. Fatigue can range from mild to severe and can affect every 
area of life. Conclusively, American and European guidelines (American Association for the Study 
of Liver Diseases [AASLD], European Association for the Study of the Liver [EASL]) rank the 
treatment of HCV-related debilitating fatigue as a high priority [20, 21]. Importantly, this symptom 
is difficult to quantify objectively and occurs independently from severe liver damage. In addition, 
there is a lack of controlled studies investigating fatigue in HCV patients [22]. Specifically on the 
effect of 3D regimen, there is a data gap on the association of treatment success and the 
improvement of fatigue. 
Therapy of HCV has seen huge progress in recent years. Viekirax® (ombitasvir/ paritaprevir/ 
ritonavir tablets) is indicated in combination with Exviera® (dasabuvir tablets) with or without 
Ribavirin (RBV) for the treatment of chronic hepatitis C in adults, genotype 1. Combination 
treatment (3D regimen) combines three different antiviral mode of action and has been shown to 
result in sustained virologic response (SVR) rates higher than 95 percent [23-25].  
Rationale 
Data demonstrating a longitudinal change of debilitating physical fatigue, along with concurrently 
increased daytime physical activity upon treatment with 3D regimen are missing to date and are 
highly anticipated by the Swiss scientific HCV community. 
Furthermore, this study attempts to support the widely discussed Swiss Hepatitis Strategy, which 
seeks for the elimination of viral hepatitis in Switzerland within the next 15 years by creating 
awareness for patients with extrahepatic manifestations [3]. 

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8.0 
Research Question and Objectives 
8.1 
Research Question 
Does successful treatment with 3D regimen increase total daytime physical activity and reduce 
fatigue in HCV-positive patients? 
8.2 
Objectives 
8.2.1 
Primary Objective 
• 
To observe changes in physical activity in patients with newly initiated therapy with 3D 
regimen between baseline (before treatment start) and post-treatment week 12 
8.2.2 
Secondary Objectives 
• 
To correlate subjective fatigue (assessed by means of FSS) and physical activity 
(measured with an electronic activity tracker) at baseline, during and after 12 weeks of 
treatment with 3D regimen  
• 
To observe the proportion of patients achieving sustained virologic response (SVR12) 
after treatment with 3D regimen (defined as HCV RNA not detectable, 12 weeks after the 
last dose of 3D regimen) 
• 
To observe sleep efficiency (assessed by means of activity tracker) at baseline, during 
and after 12 weeks of treatment with 3D regimen  
 
9.0 
Research Methods 
9.1 
Study Design 
This prospective, multicenter, post-marketing observational study (PMOS) will be conducted with 
a single arm design on HCV patients receiving 3D regimen according to routine clinical practice. 
This study will be conducted in the main Swiss HCV competence centers. 

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The decision of the treatment regimen is at the discretion of the physician in accordance with local 
clinical practice and label; it is made independently from this observational study, and precedes 
the decision to offer the patient the opportunity to participate in this study.  
Adult patients diagnosed with HCV, for which the decision to treat with 3D regimen has been 
made, will be offered the opportunity to participate in this study during a routine clinical visit at the 
participating sites. 
After written informed consent has been obtained, patient data including demographic data, HCV 
disease characteristics (including questionnaire-assessed fatigue), comorbidities, concomitant 
medication, and treatment details as recorded in the patient's medical records (source 
documentation) will be documented in the case report form (CRF).  
Follow-up visits, treatment, procedures and diagnostic methods will follow physicians’ routine 
clinical practice. Patients will be observed for approximately 28 weeks. No patient identifiable 
information will be captured; a unique patient number will be specified in the CRF. 
The study activities to be conducted are outlined in the schematic presented below. 
 

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Figure 1: Study Activities 
 
9.1.1 
Description of Activities 
Patients will be screened to ensure they meet the inclusion criteria. All patients will be required to 
sign an informed consent to use and disclose personal health information. By signing this 
consent, patients agree to release their information to AbbVie. No study related activity will be 
performed prior to obtaining written informed consent.

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When the investigator has determined that the patient is eligible for participation, and the patient 
has agreed to be included in this observational study, the patient will be handed out his personal 
activity tracker (ActiGraph GT9X Link [26]) (Figure 1) and will be instructed in its use. The patient 
will be advised to report any potential side effects related to the activity tracker, such as possible 
discomfort wearing the device around the clock or possible skin rash or skin irritation, to the study 
personnel. ActiGraph GT9X Link has a data storage capacity of 240 days/4GB. Therefore, the 
patient will keep the tracker for the whole duration of the study (196 days). The patients will be 
requested to start wearing their activity trackers on the non-dominant arm constantly for 8 weeks 
between visit 1 and visit 3 and for 4 weeks preceding visits 4 and 5. Everytime the patient has to 
put on his tracker, he will receive a reminder call from a local study personnel to increase 
adherence. At the last visit, the investigator will collect the tracker and deliver it to the 
biostatistician which in turn transfers the activity data to a post-processed environment (ActiLife 6 
[27]) (Figure 1). 
If the investigator sees the medical indication to initiate treatment with 3D regimen before the 
patient has worn the activity tracker for at least 4 weeks during the treatment preparation phase, 
or if 3D regimen is discontinued at the investigator’s discretion, the patient will discontinue study 
participation. ActiGraph GT9X Link comes with a wear time sensor that automatically detects if a 
wrist worn device has been removed. Thus, patient compliance to the tracker will be measured by 
this wear time sensor. If values are missing for a total of ≥ 2 hours during daytime, this day will be 
declared as non-eligible. In order to complete the data set of 2 weeks (10 working days) any non-
eligible day will be replaced by daytime values in a pre-defined order, starting with the most recent 
day of the respective aforegoing week (Figure 1). Weekend days are excluded from analysis.  
 
Health Outcomes Assessment 
Activity Tracker: ActiGraph GT9X Link (Annex 1) [26] 
The ActiGraph GT9X Link has been classified as Class I medical device within the European 
Union and allows to deliver valuable information about movement, rotation, and body position.  

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There have been already published several examples of the use of ActiGraph devices in research 
studies and clinical trials involving physical activity, energy expenditure, and sleep/wake behavior 
and their relationships to a wide range of health conditions including HCV, obesity, diabetes, 
cancer, CNS disorders, cardiovascular disease and sleep disorders. [28-37]. 
The collected activity data can be utilized in a post-processed environment (ActiLife 6). Data is 
automatically collected from all on-board sensors in raw data format (Annex 1).  
After a profound training on the tracker (activity monitor, software ActiLife 6) the local study 
personnel will be in charge to help and instruct patients correctly in the use and requirements to 
stay in the study, as well as to assist in the case of tracker-related questions that may arise. 
Furthermore, a detailed patient information brochure will give useful information about the tracker 
handling to the patient. 
Questionnaire 
Patients will be asked to complete the Fatigue Severity Scale (FSS) before treatment start and at 
each visit as part of routine practice. The FSS is a nine-item questionnaire assessing the 
functional impact of fatigue during the past two weeks on multiple life domains using scales from 1 
(strongly disagree) to 7 (strongly agree). The fatigue score is the mean score of the 9 items. 
Clinically significant fatigue is usually defined as score equal or above “4” [38, 39]. The routinely 
assessed FSS score to be used within this study should not include questionnaire results older 
than 3 months before visit 1. Patients with an average FSS score < 4 at visit 2 will discontinue 
study participation.
 

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Specifically, the following termination criteria apply: 
x 
Patients not eligible for treatment with 3D regimen in accordance with the Swiss product 
label and according to the investigator’s judgment will discontinue study participation.  
x 
Patients who discontinue treatment with 3D regimen or who do not wear the activity 
tracker for at least 3 weeks before each visit will be withdrawn from the study. In case the 
decision to discontinue treatment with 3D regimen was taken before or during a routine 
clinic visit, this visit will be considered the last study visit. The last dose of treatment of 3D 
regimen will be recorded in the CRF.  
x 
Patients with an average FSS score < 4 at visit 2 will discontinue the study.  
 
Following discontinuation of the study, the patient will be treated in accordance with the 
investigator's best clinical judgment. 
 
9.2 
Setting
9.2.1 
Target Population 
Patients are eligible for observation in this study, if the following applies:  
Inclusion Criteria: 
x 
Male and female patients aged ≥ 18 years  
x 
Treatment-naïve patients 
x 
Patients monoinfected with CHCV, GT1 (confirmed within the last 36 months or at 
physicians discretion in case of risk factors) 
x 
Non-cirrhotic patients (based on liver biopsy, fibroscan ≤ 9.6kPa and/or clinical signs) 
x 
The decision to treat with 3D regimen is made by the physician in accordance with the 
local Swiss product label prior to any decision to approach the patient to participate in this 
study. 
x 
Patients with debilitating fatigue (FSS ≥ 4) 

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x 
Patients willing to participate in the study, and willing to wear an activity tracker 
Exclusion Criteria:  
x 
Patients with sources of fatigue other than HCV (especially, severe depression (Annex 4), 
cancer and hormonal disorders causing clinically significant fatigue)  
x 
Patients with conditions that do not allow to adhere to protocol and use of the device at 
investigator's discretion 
x 
Patients being wheelchair dependent 
9.2.2 
Study Duration 
This is a prospective, observational study. The enrollment period will be approximately 12 months 
and the duration of the observational period will be approximately 28 weeks for each patient. 
Patients may discontinue treatment or the study at any time without prejudice. 
 
9.2.3 
Investigator Selection Criteria 
The sites will be selected based on the availability of patient population targeted for this study. 
The selected investigators (qualified by training and experience) and study sites (with proven 
experience and competence in treating HCV patients) will have the ability to appropriately conduct 
this observational study in accordance with applicable legal and regulatory requirements. 
 
9.3 
Variables 
9.3.1 
Primary Variable 
x 
Change of mean daytime physical activity between baseline (before treatment start) and 
post-treatment week 12 
 

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9.3.2 
Secondary Variables 
x 
Change of Fatigue Severity Score (FSS) between baseline, during and after 12 weeks of 
treatment with 3D regimen  
x 
Correlation between mean daytime physical activity and FSS at baseline, during and after 
12 weeks of treatment with 3D regimen  
x 
Proportion of patients achieving SVR12 after treatment with 3D regimen (defined as HCV 
RNA not detectable 12 weeks after the last actual dose of 3D regimen)  
x 
Sleep efficiency at baseline, during and after 12 weeks of treatment with 3D regimen   
 
9.4 
Data Sources 
Source documents are defined as original documents. The investigator will document patient data, 
including FSS, in his/her own patient files which will serve as source data for the study. Physical 
activity and sleep data will be collected by use of wrist-worn activity trackers (ActiGraph GT9X 
Link) which will be processed by device-specific software to obtain the physical activity and sleep-
related variables for analysis. 
All data collected by the activity tracker will be analyzed by the biostatistician at the end of the 
study. The data will not be seen by the investigators and patients at any time during data 
collection (between visit 1 and visit 5 (Figure 1: Study Activities).  
 
9.5 
Study Size 
Observational research is exploratory in nature and there are no pre-specified hypotheses to be 
tested. Hence, there is no need for power calculation. The primary endpoint in this study is derived 
from an activity tracking device.  

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In the literature, no data on actigraphy in HCV patients suffering from fatigue are available that 
would allow statistical sample size calculation focusing on the precision of estimation of the 
primary endpoint.  
On the other hand, the patient selection criteria only allow recruitment of a restricted number of 
patients in a justifiable period of time. We assume that a total of 100 patients are sufficient to 
provide stable results regarding investigation of the study objectives. 
The planned study size of 100 will have 80% power to detect a change from baseline of the effect 
size 0.29 using a two-sided one-sample t-test with a significance level of 5%. 
 
9.6 
Data Management 
Data for this study will be recorded in English by each participating center on case report forms 
(CRFs). Examinations, diagnostic measures, laboratory assessments, findings and observations 
routinely performed in this cohort, will be transcribed by the investigator or designee from the 
source documents into the CRF. Only data specified in the observational plan will be entered into 
the CRF. For each enrolled patient, the investigator or designee will create a new patient file in the 
CRF.  
The investigator or designee will deliver the activity tracker to the study designated biostatistician 
following the last scheduled patient visit (Table 1). Activity tracker collected data will then be 
transferred to the data processing software ActiLife 6 [27].  
Besides the tracker data, CRF data will be evaluated by a study designated biostatistician.  
9.7 
Data Analysis 
All data will be analyzed by descriptive statistical methods.  

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Quantitative data (e.g. the primary variable) will be analyzed by the statistical parameters valid N, 
missing N, mean, standard deviation (SD), and selected quantiles: minimum (0%), lower quartile 
(25%), median (50%), upper quartile (75%), and maximum (100%). If indicated by the data, an 
additional frequency distribution will be supplied after appropriate grouping of data. 
Qualitative (e.g. achievement of SVR12 (yes/no)) and categorical variables (e.g. individual items 
of the FSS) will be presented by (absolute and relative) frequency distributions. 
The primary variable will be tested using the one-sample t-test (two-sided) on the 5% significance 
level. 
Two-sided 95% confidence intervals will be provided for mean daytime physical activity, FSS and 
sleep efficiency by visit and for the changes between start of treatment and the respective follow-
up visits. A 95% confidence interval for the proportion of patients achieving SVR12 will also be 
calculated. 
The correlation between the physical activity (assessed by the activity tracker) and the fatigue 
score (assessed by FSS) will be investigated by visit and for the changes between baseline and 
follow-up visits, using Spearman's rank correlation coefficient. 
Subgroup analyses will be provided for patients who achieve / do not achieve SVR12 after 
treatment with 3D regimen. 
All statistical analyses will be carried out by means of the SAS® package (version 9.2 or higher). 
Details of planned analyses will be described in a separate statistical analysis plan (SAP). 
9.8 
Quality Control 
The sites will be instructed in the observational plan, the handling of the CRF and activity tracker, 
and the requirement to maintain source documents for each patient in the study (see Section 9.4).  

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Follow-up on CRF data for medical plausibility will be done by AbbVie personnel (or their 
representatives). The investigator of each site will finally review the CRFs for completeness and 
accuracy of available data and provide his or her signature and date to CRFs as evidence thereof.  
Continuous monitoring of the study and frequent site telephone contacts will be done by AbbVie or 
a Contract Research Organization (CRO) working on behalf of AbbVie. 
Patients will not be compensated for their participation in this PMOS study. Participating 
physicians will be offered compensation by AbbVie for compiling and submitting clinical 
information for use in this PMOS study  according to the regulatory requirements in 
Switzerland.  In case of inconsistent data entry, the physician will be contacted during query 
management to complete data of concerned visits. Without complete documentation only partial 
payment of visits will be performed. Amount of payment per Visit will be documented in contracts 
between participating site and AbbVie. 
 
9.9 
Limitations of the Research Methods 
The limitations of observational studies, such as uncontrolled confounding by lack of 
randomization, and difficulties to clearly interpret treatment effects in the context of missing data 
are well known. Their validity can be increased by accurate outcome measurements, 
documentation of the most common confounders, sufficient length of follow-up and by activities to 
obtain complete recording of available data as well as by searches for missing key data.  
The most important outcome measure in this study is the measurement of physical activity by the 
ActiGraph GT9X Link. Failure in wearing the device or misuse may lead to erroneous estimation 
of the real physical activity pattern of the respective patient.  
 

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9.10 
Other Aspects 
N/A 
10.0 
Protection of Human Subjects 
This observational study will be run in compliance with local laws and regulations. 
Notification/submission to the responsible regulatory authorities, Ethics Committee (EC) and/or 
Competent Authorities (CAs) will be done as required by local laws and regulations. 
The investigator is responsible to ensure that written informed consent to use and/or disclose 
patients’ anonymized health data will be obtained prior to patient inclusion.  
To maintain patient confidentiality, no demographic data that can identify the patient will be 
collected (e.g. initials, date of birth) - only the patient age will be collected. In order to protect 
patient identity, a unique number will be assigned to each patient and related study records. 
The study will be entirely financed by AbbVie AG. The patient will not be paid for his participation 
in the study. 
 
11.0 
Management and Reporting of Complaints 
A Complaint is any written, electronic, or oral communication that alleges deficiencies related to 
the physical characteristics, identity, quality, purity, potency, durability, reliability, safety, 
effectiveness, or performance of a product/device after it is released for distribution. 
Complaints associated with any component of this product/device must be reported to the 
Sponsor (Section 11.2.2). For adverse events, please refer to Sections 11.1.1 through 11.1.7. For 
product complaints, please refer to Section 11.2. 
 

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11.1 
Medical Complaints 
11.1.1 
Adverse Event Definition and Serious Adverse Event 
Categories 
An adverse event (AE) is defined as any untoward medical occurrence in a patient, which does 
not necessarily have a causal relationship with their treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 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. 
Such an event can result from use of the drug as stipulated in the labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-
existing condition or illness is considered an AE. An AE can also derive from the medical device 
ActiGraph GT9X Link, which is used in this study. Minimal risks related to the Activity Tracker can 
be possible discomfort wearing the device around the clock and possible skin rash or skin irritation 
caused by the device. 
Patient reported FSS questionnaire data are not considered a potential source of adverse 
reactions. However, participating sites should review the questionnaire data and if a possible 
product-related event (including a suspected adverse reaction) is noted, the Health Care 
Professional must determine whether the event is related to an AbbVie authorized product and if 
so, it should be reported to AbbVie. If an increase in the FSS score by ≥ 1 point is observed, the 
investigator must report this increased fatigue as an AE to AbbVie. 
Patient derived activity tracker data are not considered a potential source of adverse reactions. 
Physicians are not able to see tracker data at any time. Thus, if a possible product-related event 
(including a suspected adverse reaction) is noted, activity tracker derived mean values of interest 
will be reported exclusively at the end of the study by the bio-statistician to the AbbVie PV team. 
If an AE meets any of the following criteria, it is considered a serious adverse event (SAE): 

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Death of Patient: 
An event that results in the death of a patient. 
Life-Threatening: 
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken. This does not include an event that would 
have been fatal if it had occurred in a more severe form. 
Hospitalization: 
An event that results in an admission to the hospital for any 
length of time. This does not include an emergency room 
visit or admission to an outpatient facility. 
Prolongation of 
Hospitalization: 
An event that occurs while the study patient is hospitalized 
and prolongs the patient's hospital stay. 
Congenital Anomaly: 
An anomaly detected at or after birth or any anomaly that 
results in fetal loss. 
Persistent or Significant 
Disability/Incapacity: 
An event that results in a condition that substantially 
interferes with the activities of daily living of a study patient. 
Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle). 
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome: 
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the patient and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of patient, life 
threatening, hospitalization, prolongation of hospitalization, 
congenital anomaly, or persistent or significant 
disability/incapacity). Additionally, any elective or 

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spontaneous abortion or stillbirth is considered an 
important medical event. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
 
11.1.2 
Severity 
The following definitions will be used to rate the severity for any AE being collected as an 
endpoint/data point in the study and for all SAEs. 
Mild:
The AE is transient and easily tolerated by the patient. 
Moderate: 
The AE causes the patient discomfort and interrupts the patient's usual 
activities. 
Severe: 
The AE causes considerable interference with the patient's usual 
activities and may be incapacitating or life threatening. 
 
11.1.3 
Relationship to Pharmaceutical Product 
The following definitions will be used to assess the relationship of the adverse event to the use of 
product: 
Reasonable Possibility 
An AE where there is evidence to suggest a causal 
relationship between the product and the adverse event. 
No Reasonable Possibility 
An AE where there is no evidence to suggest a causal 

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relationship between the product and the adverse event. 
 
If no reasonable possibility of being related to product is given, an alternate etiology must be 
provided for the AE. 
11.1.4 
Serious-, non Serious Adverse Event and Pregnancy 
Collection Period 
SAE, AE and pregnancy will be reported to AbbVie from the time the physician obtains the 
patient's authorization to use and disclose information (or the patient's informed consent) until 30 
days or 5 half-lives following the intake of the last dose of physician-prescribed treatment, which 
ever period is longer. 
 
11.1.5 
Adverse Event reporting 
For events from patients using and AbbVie product - notify the AbbVie contact person identified 
below within 5 business days of the physician becoming aware of the event. 
11.1.6 
Serious Adverse Event Reporting 
For events from patients using and AbbVie product - notify the AbbVie contact person identified 
below within 24 hours of the physician becoming aware of the event. 

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11.1.7 
Pregnancy Reporting 
In the event of a pregnancy occurrence in the female patient or in the female partner of a male 
patient, the physician will notify AbbVie contact person identified in Section 11.1.6 within 24 hours 
of the physician becoming aware of the pregnancy. 
 
11.2 
Product Complaint 
11.2.1 
Definition 
A Product Complaint is any Complaint (see Section 11.0 for the definition) related to the biologic 
or drug component of the product. A Product Complaint can also derive from the medical device 
ActiGraph GT9X Link, which is used in this study. 
For a product this may include, but is not limited to, damaged/broken product or packaging, 
product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example: printing illegible), missing 
components/product, or packaging issues. 
Any information available to help in the determination of causality to the events outlined directly 
above should be captured. 

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11.2.2 
Reporting 
Product Complaints concerning the product/ device must be reported to the Sponsor within 24 
hours of the study site's knowledge of the event via local Product Complaint reporting practices. 
Product Complaints occurring during the study will be followed-up to a satisfactory conclusion. All 
follow-up information is to be reported to the Sponsor (or an authorized representative) and 
documented in source as required by the Sponsor. Product Complaints associated with adverse 
events will be reported in the study summary. All other complaints will be monitored on an ongoing 
basis. 
Product complaints involving a non-Sponsor product / device should be reported to the identified 
contact or manufacturer, as necessary per local regulations. 
Product Complaints may require return of the product/ device with the alleged complaint condition. 
In instances where a return is requested, every effort should be made by the investigator to return 
the product within 30 days. If returns cannot be accommodated within 30 days, the site will need 
to provide justification and an estimated date of return. 
The description of the complaint is important for AbbVie in order to enable AbbVie to investigate 
and determine if any corrective actions are required. 
12.0 
Plans for Disseminating and Communicating Study 
Results
At the end of this observational study, a report will be written by AbbVie or a CRO working on 
behalf of AbbVie. The required standard study report template will be followed. This report will 
contain a description of the objectives of the study, the methodology and its results and 
conclusions. The completed CRFs, [patient questionnaires, interim assessments], the final study 
output and study report are the confidential property of AbbVie and may not be released to 
unauthorized people in any form (publications or presentations) without express written approval 
from AbbVie. The study results will be submitted to local authorities per local laws and regulations. 

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The results of this study will be made publicly available on one of the primary registries in the 
World Health Organization (WHO) Registry Journal Network which meet the requirements of the 
International Committee of Medical Editors (ICMJE) and through scientific publications. Authorship 
will be in line with ICMJE’ authorship requirements [40].  
 
 

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13.0 
References 
1. 
Negro, F., et al., Extrahepatic morbidity and mortality of chronic hepatitis C.
Gastroenterology, 2015. 149(6): p. 1345-1360. 
2. 
Swiss Association for the Study of the Liver (SASL), SASL-SSI Expert Opinion 
Statement on the Treatment of Chronic Hepatitis C - January 2016 Update. 2016: 
Available Online at https://sasl.unibas.ch/6SASLguidelines.php, accessed 9 June 
2016. 
3. 
Swiss Experts in Viral Hepatitis (SEVHep), Swiss National Strategy to Combat 
Chronic Viral Hepatitis. 2015: Available online, at www.hepatitis-
schweiz.ch/files/Dokumente/Process_Paper_2nd_version_final.pdf, accessed 9 
June 2016. 
4. 
Summary of Product Characteristics for Viekirax® 
(ombitasvir/paritaprevir/ritonavir) and Exviera® (dasabuvir); February 2016 
(Exviera), March 2016 (Viekirax). Available online, at www.swissmedicinfo.ch.
5. 
Lavanchy, D., The global burden of hepatitis C. Liver Int, 2009. 29 Suppl 1: p. 
74-81. 
6. 
Messina, J.P., et al., Global distribution and prevalence of hepatitis C virus 
genotypes. Hepatology, 2015. 61(1): p. 77-87. 
7. 
Ahmed, N.H. and M.H. Emara, Extrahepatic Manifestations of Hepatitis C Virus: 
An Extending List. Afro-Egyptian Journal of Infectious and Endemic Diseases, 
2012: p. 36. 
8. 
Kraus, M.R., et al., Improvement of neurocognitive function in responders to an 
antiviral therapy for chronic hepatitis C. Hepatology, 2013. 58(2): p. 497-504. 
9. 
Pattullo, V., et al., Influence of hepatitis C virus on neurocognitive function in 
patients free from other risk factors: validation from therapeutic outcomes. Liver 
Int, 2011. 31(7): p. 1028-38. 
10. 
Bajaj, J.S., The role of microbiota in hepatic encephalopathy. Gut Microbes, 2014. 
5(3): p. 397-403. 
11. 
Wilkinson, J., et al., Activation of brain macrophages/microglia cells in hepatitis 
C infection. Gut, 2010. 59(10): p. 1394-1400. 
12. 
Rosenberg, S.D., et al., Prevalence of HIV, hepatitis B, and hepatitis C in people 
with severe mental illness. American journal of public health, 2001. 91(1): p. 31. 
13. 
McAndrews, M.P., et al., Prevalence and significance of neurocognitive 
dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology, 
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14. 
Schaefer, M., et al., Hepatitis C infection, antiviral treatment and mental health: a 
European expert consensus statement. Journal of hepatology, 2012. 57(6): p. 
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15. 
Poordad, F.F., Review article: the burden of hepatic encephalopathy. Aliment 
Pharmacol Ther, 2007. 25 Suppl 1: p. 3-9. 
16. 
Monaco, S., et al., HCV-related nervous system disorders. Clinical and 
Developmental Immunology, 2012. 2012.
17. 
Lang, C.A., et al., Symptom prevalence and clustering of symptoms in people 
living with chronic hepatitis C infection. Journal of Pain and Symptom 
Management, 2006. 31(4): p. 335-344. 
18. 
Poynard, T., et al., Fatigue in patients with chronic hepatitis C. Journal of viral 
hepatitis, 2002. 9(4): p. 295-303. 
19. 
Carlson, M.D., et al., Role of Sleep Disturbance in Chronic Hepatitis C Infection.
Current Hepatitis Reports, 2010. 9(1): p. 25-29. 
20. 
AASLD-IDSA HCV Guidance Panel, Hepatitis C guidance: AASLD-IDSA 
recommendations for testing, managing, and treating adults infected with hepatitis 
C virus. Hepatology, 2015. 62(3): p. 932-54. 
21. 
European Association for the Study of the Liver (EASL), EASL Recommendations 
on Treatment of Hepatitis C 2015. J Hepatol, 2015. 63(1): p. 199-236. 
22. 
Sarkar, S., et al., Fatigue before, during and after antiviral therapy of chronic 
hepatitis C: results from the Virahep-C study. J Hepatol, 2012. 57(5): p. 946-52. 
23. 
Ferenci, P., et al., ABT-450/r-ombitasvir and dasabuvir with or without ribavirin 
for HCV. N Engl J Med, 2014. 370(21): p. 1983-92. 
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Feld, J.J., et al., Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with 
ribavirin. N Engl J Med, 2014. 370(17): p. 1594-603. 
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Poordad, F., et al., ABT-450/r-ombitasvir and dasabuvir with ribavirin for 
hepatitis C with cirrhosis. N Engl J Med, 2014. 370(21): p. 1973-82. 
26. 
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27. 
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28. 
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Heeren, M., et al., Active at night, sleepy all day–Sleep disturbances in patients 
with hepatitis C virus infection. Journal of hepatology, 2014. 60(4): p. 732-740. 
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Chau, J.Y., et al., More standing and just as productive: Effects of a sit-stand desk 
intervention on call center workers’ sitting, standing, and productivity at work in 
the Opt to Stand pilot study. Preventive Medicine Reports, 2016. 3: p. 68-74. 
31. 
Pawlowski, C.S., et al. Children's physical activity behavior during school recess: 
A case study using GPS, accelerometer, participant observation, and go-along 
interview. in Poster session presented at the congress: International Society of 
Behavioral Nutrition and Physical Activity, Edinburgh, Scotland. 2015. 

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32. 
Clemente, F.M., et al., Physical Activity Patterns in University Students: Do They 
Follow the Public Health Guidelines? PloS one, 2016. 11(3): p. e0152516. 
33. 
Wick, K., et al., Deviation between self-reported and measured occupational 
physical activity levels in office employees: effects of age and body composition.
International archives of occupational and environmental health, 2015: p. 1-8. 
34. 
Donath, L., et al., Repetitive Daily Point of Choice Prompts and Occupational Sit-
Stand Transfers, Concentration and Neuromuscular Performance in Office 
Workers: An RCT. International journal of environmental research and public 
health, 2015. 12(4): p. 4340-4353. 
35. 
Burns, R.D., et al., Establishing school day pedometer step count cut-points using 
ROC curves in low-income children. Preventive medicine, 2016. 86: p. 117-122. 
36. 
Schall, M.C., N.B. Fethke, and H. Chen, Evaluation of four sensor locations for 
physical activity assessment. Applied ergonomics, 2016. 53: p. 103-109. 
37. 
Slater, J.A., et al., Assessing sleep using hip and wrist actigraphy. Sleep and 
Biological Rhythms, 2015. 13(2): p. 172-180. 
38. 
Kleinman, L., et al., Psychometric evaluation of the fatigue severity scale for use 
in chronic hepatitis C. Qual Life Res, 2000. 9(5): p. 499-508. 
39. 
Rosa, K., et al., Validation of the Fatigue Severity Scale in chronic hepatitis C.
Health and quality of life outcomes, 2014. 12(1): p. 1. 
40. 
International Committee of Medical Journal Editors, Defining the role of authors 
an contributors. Available at 
http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html, accessed 19 
May 2016. 
41. 
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http://apps.who.int/classifications/icd10/browse/2016/en#/F32.2, accessed 07 July 
2016.
 
 

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ActiGraph GT9X Link: Regulatory Requirements  
x The ActiGraph Link is a Class I medical device within the European Union that abides by the 
regulatory requirements listed below:EN60601-1-Medical Device General Safety Requirements 
x Part 15.109 (US) – Radiated Emission Limits of Unintentional RadiatorsPart 15.249 (US) – 
Radiated Emission Limits of Intentional Radiators 
x ICES-003 (Canada) – Interference Causing Equipment Standards for a Digital Apparatus. 
x ActiGraph is compliant with IEC standards for “Type BF Applied Part” 
x ActiGraph Link and ActiGraph wGT3X-BT is water resistant in accordance with IEC 60529 
IPX7, or immersion in one (1) meter of water for up to 30 minutes. 
x All ActiGraph products are manufactured Lead Free and are RoHS Compliant. 
Specifications 
Dimensions  
3.5 x 3.5 x 1 cm  
Weight  
14 grams  
Sample Rate  
30-100 Hertz  
Dynamic Range (Primary Accelerometer)  
+/- 8G  
Dynamic Range (Secondary Accelerometer)  
+/- 16G  
Gyroscope Dynamic Range  
+/- 2000 deg/sec  
Magnetometer Dynamic Range  
+/- 4800 micro-Tesla  
Battery Life  
14 days*  
Data Storage  
240 days / 4 GB  
Communication  
USB, Bluetooth® LE  
Water Resistance  
1 meter, 30 minutes  
Wear Location  
Wrist, waist  
Warranty 
1 year  
*Wireless disabled, 30 Hz sample rate, gyro disabled, sleep mode 
 
 
 

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Annex 2. 
Fatigue Severity Scale (FSS) [38]
Below are a series of statements regarding your fatigue. By fatigue we mean a sense of tiredness, 
lack of energy or total body give-out.  
Please read each statement and choose a number from 1 to 7, where # 1 indicates you 
completely disagree with the statement and # 7 indicates you completely agree.  
 
Please answer these questions as they apply to the past TWO WEEKS. 
 
 
Completely                               Completely 
Disagree                                           Agree
1. My motivation is lower when I am fatigued 
1 
2 
3 
4 
5 
6 
7 
2. Exercise brings on my fatigue 
1 
2 
3 
4 
5 
6 
7 
3. I am easily fatigued 
1 
2 
3 
4 
5 
6 
7 
4. Fatigue interferes with my physical functioning 
1 
2 
3 
4 
5 
6 
7 
5. Fatigue causes frequent problems for me 
1 
2 
3 
4 
5 
6 
7 
6. My fatigue prevents sustained physical functioning 
1 
2 
3 
4 
5 
6 
7 
7. Fatigue interferes with carrying out certain duties and responsibilities 
1 
2 
3 
4 
5 
6 
7 
8. Fatigue is among my 3 most disabling symptoms 
1 
2 
3 
4 
5 
6 
7 
9. Fatigue interferes with my work, family, or social life 
1 
2 
3 
4 
5 
6 
7 

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Annex 3. 
ICD-10 Version:2016 [41]