A Multi-country Time and Motion Study to Describe the Experience of Clinicians, Patients and Their Caregivers During the Treatment of Fabry Disease With Enzyme Replacement Therapy With Agalsidase Alfa and Agalsidase Beta
Conditions: Fabry Disease
Sponsor: Amicus Therapeutics

 
 
 
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STUDY PROTOCOL 
Study title 
A multi-country time and motion study to describe the experience of 
clinicians, patients and their caregivers during the treatment of Fabry 
Disease with Enzyme Replacement Therapy with agalsidase alfa and 
agalsidase beta 
 
Short title 
A study to describe the experience of both patients and their 
clinicians in the treatment of Fabry Disease with Enzyme 
Replacement Therapy. 
Study Sponsor 
Amicus Therapeutics 
Key Sponsor contact 
 
Associate Director Global Market Access  
 
 
Study Management 
Company 
Open Health 
The Weighbridge, 
Brewery Courtyard 
High Street 
Marlow, SL7 2FF 
Country(-ies) 
of 
study 
 Taiwan, Turkey, Brazil, and Japan 
Protocol version 
Final V4 
Date 
23 March 2020 
 
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Confidentiality Notice 
This document contains confidential, trade secret, and/or proprietary information of Open 
Health and Amicus Therapeutics. 
This document must not be disclosed to anyone other than the study staff and members of 
the local competent authority and independent ethics committee. 
The information in this document cannot be used for any purpose other than the evaluation 
or conduct of the study without the prior written consent of Open Health and Amicus 
Therapeutics. 
 
 
 
 
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APPROVAL SIGNATURE PAGE 
 
On behalf of the sponsor, Amicus Therapeutics:  
NAME: 
 
TITLE: 
Executive Director, Global Medical Lead, Fabry Disease 
SIGNATURE: 
DATE: 
 
 
 
NAME: 
 
TITLE: 
Associate Director, Global Market Access 
SIGNATURE: 
DATE: 
 
 
 
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INVESTIGATOR APPROVAL SIGNATURE PAGE 
 
On behalf of the Principal Investigator at each site:  
 
I have carefully read this protocol entitled “A multi-country time and motion study to describe 
the experience of clinicians, patients and their caregivers during the treatment of Fabry 
Disease with Enzyme Replacement Therapy with agalsidase alfa and agalsidase beta”, and 
agree that it contains all the necessary information required to conduct the study. I agree to 
conduct this study as outlined in the protocol. 
 
NAME: 
 
TITLE: 
SIGNATURE:  
DATE: 
 
 
 
 
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Table of contents 
Table of contents .................................................................................................................... 5 
List of tables ............................................................................................................................ 6 
1. 
List of abbreviations .................................................................................................... 7 
2. 
Key definitions ............................................................................................................. 9 
3. 
Responsible parties ..................................................................................................... 9 
4. 
Abstract ..................................................................................................................... 10 
5. 
Study amendments and updates .............................................................................. 16 
6. 
Milestones ................................................................................................................. 18 
7. 
Rationale and background ........................................................................................ 18 
8. 
Research questions and objectives ........................................................................... 20 
8.1 
Research questions ................................................................................................... 20 
8.2 
Hypothesis ................................................................................................................. 20 
8.3 
Primary objective ...................................................................................................... 20 
8.4 
Secondary objectives................................................................................................. 20 
9. 
Research methods ..................................................................................................... 21 
9.1 
Study design .............................................................................................................. 21 
9.1.1    Prospective time and motion study .......................................................................... 22 
9.1.2    Cross sectional evaluation of patient- and caregiver-reported outcome measures 23 
9.2 
Setting........................................................................................................................ 25 
9.3       Study time periods ..................................................................................................... 27 
9.4       Study population........................................................................................................ 27 
9.4.1    Selection criteria for patients .................................................................................... 27 
9.4.2    Selection criteria for caregivers................................................................................. 28 
9.4.3    Selection criteria for staff (for time and motion study) ............................................ 28 
9.5 
Patient identification, sampling and recruitment ..................................................... 29 
9.6 
Variables .................................................................................................................... 30 
9.7 
Data source................................................................................................................ 43 
9.8 
Study size ................................................................................................................... 44 
9.9 
Data management ..................................................................................................... 47 
9.9.1    Data collection ........................................................................................................... 47 
9.9.2    Data analysis .............................................................................................................. 48 
9.9.3    Missing data .............................................................................................................. 49 
9.9.4    Subgroup and sensitivity analyses............................................................................. 50 
9.9.5    Interim analyses ........................................................................................................ 50 
9.10 
Quality control........................................................................................................... 50 
9.11 
Limitations of the research methods ........................................................................ 51 
10. 
Other aspects ............................................................................................................ 52 
10.1 
Review of study results ............................................................................................. 52 
10.2 
Study Amendments and Study Termination ............................................................. 52 
11. 
Protection of human subjects ................................................................................... 53 
11.1 
Ethical and regulatory approvals............................................................................... 53 
11.2 
Ethical considerations ............................................................................................... 53 
11.3 
Participant privacy ..................................................................................................... 54 
11.4 
Study Documentation and Archive ........................................................................... 55 
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12. 
Management and reporting of adverse events / adverse reactions ........................ 55 
12.1 
Definitions ................................................................................................................. 55 
12.2 
Reporting Procedures for Adverse Events ................................................................ 57 
12.2.1  Reporting Time-Frames ............................................................................................. 57 
12.2.2  Reporting methodology ............................................................................................ 58 
12.3 
Reconciliation ............................................................................................................ 58 
13. 
Plans for disseminating and communicating study results....................................... 58 
14. 
Study support ............................................................................................................ 59 
15. 
References ................................................................................................................. 60 
16. 
Annex 1 Adverse event, special situation and product complaints intake form ...... 63 
17. 
Annex 2 Study questionnaires................................................................................... 66 
 
List of tables 
Table 1. Study amendments .................................................................................................... 17 
Table 2. Study milestones ........................................................................................................ 18 
Table 3. Timeline of completion and list of questionnaires administered to patients and 
caregivers ................................................................................................................... 25 
Table 4. Endpoints and dataset required to address the study objectives ............................. 30 
Table 5. Sample size estimations ............................................................................................. 45 
 
 
 
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1. 
List of abbreviations 
Abbreviation 
Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse event 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRO 
Clinical Research Organisation 
CSI 
Caregiver Strain Index 
DMP 
Data management plan 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
eGFR 
Estimated glomerular filtration rate 
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
ERT 
Enzyme replacement therapy 
EU 
European Union 
FD 
Fabry Disease 
FDA 
Food and Drug Administration 
Gb3 
Globotriaosylceramide 
GDPR 
General Data Protection Regulation 
GI 
Gastrointestinal 
GVP 
Good Pharmacovigilance Practice 
HCP 
Healthcare Professional 
HRQoL 
Health-related quality of life 
HTA 
Health Technology Assessment 
IEC 
Independent ethics committee 
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IQR 
Interquartile range 
IRB 
Institutional review board 
ISPE 
International Society for Pharmacoepidemiology 
IV 
Intravenous 
LOE 
Lack of Effect 
LVMi 
left ventricular mass index 
MI 
Myocardial infarction 
MRI 
Magnetic Resonance Imaging 
PC 
Product Complaint  
PQC 
Product quality complaint 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SF-12 
12 Item Short Form Survey 
SF-36 
36 Item Short Form Survey 
SS 
Special Situations 
STROBE 
Strengthening the reporting of observational studies in epidemiology 
TIA 
Transient ischaemic attack 
WBC 
White Blood Cell 
WHO-5 
World Health Organization-5 Wellbeing Index 
WPAI 
Work Productivity and Activity Index 
WPAI-CG 
Work Productivity and Activity Index: Caregiver 
 
 
 
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2. 
Key definitions 
Episode of care: An episode of care is an element or part of the care or treatment pathway 
which is being studied or measured. For the purpose of this study, an episode of care will 
constitute all healthcare professional (HCP) activities involved in the preparation and 
administration of a single dose of enzyme replacement therapy (ERT) with agalsidase alfa and 
agalsidase beta, including ERT (and pre-medication) preparation, pre- and post-
administration assessment, pharmacy and clinic activities, and any follow up activities. 
 
Caregiver: in the context of this study a caregiver is defined as an individual aged 18 years or 
over who has a personal relationship with and provides informal (unpaid) care, support or 
assistance to someone diagnosed with Fabry Disease, and accompanies them to the hospital 
or treatment centre for ERT administration on one or more occasion during the study data 
collection period. For example, this may be a parent, spouse/ partner, son/ daughter, other 
relative, neighbour or friend.  
 
3. 
Responsible parties 
The names, titles, degrees, addresses and affiliations of all responsible parties, including the 
Principal Investigators, co-investigators, and a list of all participating centres, Study 
Management Company and Sponsor contacts will be maintained in a separate document. 
 
 
 
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4. 
Abstract 
Title 
A multi-country time and motion study to describe the experience of 
clinicians, patients and their caregivers during the treatment of Fabry 
Disease with Enzyme Replacement Therapy with agalsidase alfa and 
agalsidase beta 
Rationale for study 
 
Enzyme replacement therapy (ERT) with agalsidase alfa (Replagal®, 
Shire or biosimilar) or agalsidase beta (Fabrazyme®, Sanofi Genzyme or 
biosimilar) is the current mainstay of treatment for patients with Fabry 
Disease (FD). Both ERT preparations need to be administered as an 
intravenous (IV) infusion every two weeks. Migalastat (Galafold®, 
Amicus Therapeutics), an orally-administered treatment for patients 
with FD with amenable mutations, is now approved in a number of 
countries.  
As oral therapies for FD become available, there is a need for 
comprehensive information about the burden of current treatments 
from the perspective of both patients and their caregivers and 
healthcare providers, to enable them to make fully informed decisions 
about the most appropriate treatment strategy.  There is currently a 
paucity of data on the true resource burden associated with use of 
existing ERT and the wider impact of attendance for ERT on health-
related quality of life (HRQoL) and work productivity.  
The present study will address these evidence gaps by generating 
robust real world data to quantify the current burden of ERT for the 
treatment of FD across four countries. The study will utilise a time and 
motion methodology to measure the total healthcare professional 
(HCP) time associated with a single episode of ERT administration, with 
patient- and caregiver-reported outcomes including HRQoL, 
wellbeing, levels of fatigue, work productivity and the strain of 
providing care, to be collected directly from patients with FD and their 
caregivers.  The data may be utilised by Amicus Therapeutics in 
submissions to Health Technology Assessment (HTA) bodies, and will 
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be useful for HCPs to inform future treatment decisions and ongoing 
patient management. 
Research 
question 
and hypothesis  
What is the total HCP time associated with the preparation and 
administration of a single dose of ERT in patients with FD and the 
patient and caregiver time and costs associated with an ERT 
attendance? What is the impact of FD on patients’ HRQoL, wellbeing, 
levels of fatigue and work productivity? What is the burden of care 
provision for the caregivers of patients with FD and the impact on their 
work productivity? 
 
This is a descriptive study and there is no a priori hypothesis to be 
tested. 
Objectives 
 
Primary objective 
To quantify the total time spent by HCPs in the preparation and 
administration of a single dose of ERT (with agalsidase alfa and 
agalsidase beta) in patients with FD. 
 
Secondary objectives 
1. To quantify the total patient time, costs (i.e. out of pocket 
expenses) and work-related absence associated with attendances 
for the administration of a single dose of ERT (with agalsidase alfa 
and agalsidase beta) in patients with FD. 
2. To quantify the total caregiver time, costs (i.e. out of pocket 
expenses) 
and 
work-related 
absence 
associated 
with 
accompanying a patient with FD for the administration of a single 
dose of ERT (with agalsidase alfa or agalsidase beta). 
3. To describe patient-reported HRQoL (measured by the 12 Item 
Short Form Survey [SF-12]), wellbeing (measured by the World 
Health Organization-5 Wellbeing Index [WHO-5]), levels of fatigue 
(measured by a bespoke Fatigue Likert scale) and work productivity 
(measured by the Work Productivity and Activity Index [WPAI] 
questionnaire) in patients with FD treated with ERT. 
4. To describe work productivity (measured by the WPAI for 
caregivers [WPAI:CG]) and the strain of care provision (measured 
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by the Caregiver Strain Index [CSI]) in caregivers of patients with FD 
treated with ERT.  
Study design 
This is an international, non-interventional research study of adult 
patients with FD and their caregivers. The study will comprise a 
prospective time and motion evaluation and a cross-sectional 
evaluation of patient and caregiver-reported outcomes. Patients’ 
demographic characteristics will be collected from hospital medical 
records.   
For the cross-sectional evaluation of patient and caregiver-reported 
outcomes, patients with FD and their caregivers will be asked to 
complete a series of questionnaires, to include validated measures of 
HRQoL, wellbeing and work productivity (for patients) and work 
productivity and the strain of care provision (for caregivers). Patients 
and caregivers will also complete a bespoke questionnaire to evaluate 
the total time associated with attending the hospital or treatment 
centre for a single ERT administration visit, and time away from work. 
In addition, patients will also be asked about their level of fatigue using 
a bespoke Likert scale. With the exception of the work productivity 
questionnaire and Fatigue Likert scale, the study questionnaires will 
be completed at a single point in time, when the patient attends the 
hospital or treatment centre for administration of ERT. The work 
productivity questionnaire (which has a recall period of seven days, 
excluding the day of completion) will be completed twice; the first 
work productivity questionnaire will be completed 1-7 days after 
receiving a dose of ERT (ideally within 2 days), to capture a seven day 
period that includes an ERT administration visit and the second 
questionnaire will be completed on the day the patient attends the 
hospital or treatment centre to receive their next dose of ERT (to 
capture a seven day period that does not include ERT administration). 
The Fatigue Likert scale will be completed three times; during an ERT 
administration visit, on the evening of the visit and the next day.  
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Separate patient consent will be obtained for the time and motion 
evaluation and for the cross-sectional evaluation of patient-reported 
HRQoL, wellbeing, levels of fatigue and work productivity; thus, 
patients who do not wish to complete the study questionnaires will 
remain eligible for the time and motion study (and vice versa), 
provided that consent has been obtained. 
Setting 
Patients with FD who are receiving ERT and their caregivers will be 
identified and recruited from approximately 12 specialist centres in 
four countries ( Taiwan, Turkey, Brazil and Japan). 
Participants 
The target sample size for the time and motion evaluation undertaken 
as part of this study is 240 ERT episodes, including 60 ERT episodes (30 
for agalsidase alfa and 30 for agalsidase beta) in each participating 
country. Ideally, a maximum of two ERT administration episodes will 
be observed per patient; as such, at least 30 patients are expected to 
be enrolled in each country.  For countries with limited FD patient 
numbers, a review of episodes of care observed will be completed on 
an ongoing basis.  It may be determined that it is possible to observe 
three episodes per patient in these circumstances, however only two 
episodes will be observed per patient wherever possible. 
For the questionnaire evaluation, approximately 120 patients and 20 
caregivers will be expected to fill questionnaire sets (approximately 30 
patients’ and 5 caregivers’ questionnaire sets per country). 
Patient inclusion criteria 
• Patients aged 18 years old or over at time of consent. 
• Patients with a documented diagnosis of FD. 
• Patients who have received ≥4 doses of ERT (with agalsidase 
alfa or agalsidase beta) for the treatment of FD. 
• Patients who present to the participating hospital(s) or 
treatment centre(s) for administration of a dose of ERT (as part 
of their routine treatment) during the data collection period. 
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Patient exclusion criteria 
• Patients aged <18 years at time of consent 
• Patients who are unable or unwilling to give consent for study 
participation. 
• Patients whose ERT preparation and administration takes place 
exclusively in the home setting with no HCP involvement in 
preparation of the infusion. 
• For the time and motion evaluation: Patients whose ERT is 
administered by a HCP who does not consent to be observed. 
Caregiver inclusion criteria: 
• Aged 18 years of age or over at time of consent. 
• Self-identifies as a caregiver of a patient with FD for whom 
written informed consent has been obtained for inclusion in the 
study. 
Caregiver exclusion criteria 
• Caregiver (and/or the patient with FD whom they support or 
care for) is unable or unwilling to give consent for study 
participation. 
Staff inclusion criteria (for time and motion study): 
• Members of the whole care team responsible for administering 
agalsidase alfa and agalsidase beta to patients with FD.  
• Staff who have given written consent to be observed during the 
provision of care. 
Participant selection 
Consecutive eligible patients (and their caregivers) presenting at the 
participating centres during the prospective recruitment period will be 
included in the study until the required sample size (number of ERT 
episodes) is reached. For patients who are eligible to be observed 
more than once (for the time and motion study), initial consent for 
observation of up to three episodes of care will be obtained, and will 
be confirmed verbally by their HCP before the second episode of care.  
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Each patient and caregiver will only be asked to complete one set of 
questionnaires (with the exception of the work productivity 
questionnaire [which will be completed twice] and the fatigue Likert 
questionnaire [which will be completed three times], as described 
above). 
Data source(s) 
Patients’ demographic and clinical data will be sourced from patients’ 
medical records and other systems within the main (specialist) 
participating FD centres and extracted into electronic case report 
forms (eCRFs).   
For the time and motion component of the study, prospective data 
relating to HCP time associated with the preparation and 
administration of a single dose of ERT will be captured by direct 
observation of HCPs by an independent external researcher or a 
member of the patients’ care team, during the episode of care and 
recorded on a paper case report form (CRF) which will then be 
transcribed into an eCRF.  
Patient- and caregiver-reported outcomes will be reported directly by 
patients and caregivers using anonymised-coded paper-based 
questionnaires which will be transcribed into an Excel database by 
central data managers. 
Study time period(s) It is anticipated that the prospective recruitment / data collection 
period for this study will be approximately 4-5 months, starting from 
the date on which the relevant approvals to conduct the study are in 
place. A maximum of three episodes of care per patient during the 
data collection period will be included. Consenting patients with FD 
and their caregivers will be asked to complete the study 
questionnaires at the time points described above. 
Study endpoints  
Primary endpoint: Summary measures of the total time spent by HCPs 
in the preparation and administration of a single dose of ERT in patients 
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with FD; stratified by country and by ERT product (agalsidase alfa or 
agalsidase beta).   
 
Main secondary endpoints: 
• Summary measures of the time spent by HCPs on each separate 
task associated with the preparation and administration of a single 
dose of ERT (with agalsidase alfa or agalsidase beta). 
• Summary measures of the total patient time and costs associated 
with attendance for the administration of a single dose of ERT 
(with agalsidase alfa or agalsidase beta). 
• Proportion of patients with work absence due to attendance for 
this ERT episode and number of hours absent. 
• Summary measures of the total caregiver time and costs 
associated with accompanying a patient with FD for the 
administration of a single dose of ERT (with agalsidase alfa or 
agalsidase beta). 
• Proportion of caregivers with work absence due to accompanying 
the patient for this ERT episode and number of hours absent. 
• Summary measures of patients’: 
o HRQoL (SF-12 scores / responses). 
o General wellbeing (WHO-5 scores / responses). 
o Level of fatigue (Fatigue Likert scale) 
o Levels of work impairment (WPAI scores / responses). 
• Summary measures of caregivers’: 
o Levels of work impairment (WPAI-CG scores / responses). 
o Level of strain in providing care for a patient with FD (CSI 
scores / responses). 
 
5. 
Study amendments and updates 
All amendments to the protocol will be documented in Table 1. 
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Protocol deviations will be documented in a Protocol Deviation Log (maintained in a separate 
document). 
Table 1. Study amendments 
Amendment 
number 
Date 
of 
amendment 
Section 
amended 
Amendment 
description 
Reason 
for 
amendment 
1 
Click here to 
enter a date. 
 
None at present 
 
2 
Click here to 
enter a date. 
 
 
 
3 
Click here to 
enter a date. 
 
 
 
4 
Click here to 
enter a date. 
 
 
 
 
 
 
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6. 
Milestones 
Table 2. Study milestones 
Milestone 
Planned date(s)/frequency 
Planned regulatory approval activities 
Start: Jun 2019 
End: Aug 2020 
Planned start of study (date of first consent) 
Jun 2020 
Planned collection of first data point 
Jun 2020 
Planned collection of last data point 
Nov 2020 
Study progress report 1 
No progress report is planned 
Interim study report 1 
No interim analysis is planned 
Registration in EU Post-authorisation study 
Register or equivalent public database 
Clinical trials.gov; Feb 2020 
Final report of study results (end of study) 
Apr 2021 
 
7. 
Rationale and background 
Fabry disease (FD) is a rare inherited lysosomal disorder caused by deficiency or dysfunction 
of the enzyme α-galactosidase A, which leads to an accumulation of globotriaosylceramide 
(Gb3) within the lysosomes of many cell types leading to cellular dysfunction and multi-organ 
disease1. FD is associated with a number of characteristic clinical signs and symptoms 
including neuropathic pain, gastrointestinal complications, headaches, impaired sweating, 
vertigo, hearing impairment, angiokeratomas and cornea verticillata2.  Over time, FD can lead 
to irreversible organ damage and is a cause of premature renal failure, heart disease, 
cerebrovascular events and death3. As X-linked disorder, male sufferers of FD tend to be more 
severely affected than females4. Patients with FD are widely reported to have reduced health 
related quality of life (HRQoL) compared with the general population5,6 due to the debilitating 
symptoms and damage to vital organs. Increasing age, classical FD phenotype, more severe 
disease and pain have been identified as major contributors to reduced HRQoL6.  
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Enzyme replacement therapies (ERT) with agalsidase alfa (Replagal®, Shire) and with 
agalsidase beta (Fabrazyme®, Sanofi Genzyme) currently represent two treatment options for 
patients with FD and have been shown to reduce substrate levels in several cell types. In 
addition there are reports of reductions in the severity of neuropathic pain, stabilization of 
renal and cardiac function and delay in the occurrence of serious complications7–10. However, 
both ERT preparations need to be administered as an intravenous (IV) infusion every two 
weeks and therefore lifelong ERT places a considerable burden on patients, their caregivers 
and healthcare services.  ERT administered in the hospital or clinic setting requires frequent 
visits for IV infusions, which many patients find stressful and inconvenient; furthermore, 
hospital-based treatment often takes place in a specialist FD centre, which may be a 
considerable distance from the patient’s home11,12.  In some countries ERT can be 
administered in the patient’s home under certain circumstances (for example, if the patient 
has stable disease and experienced no adverse reactions during hospital-based infusion) and 
this is generally perceived to be more convenient than hospital-based therapy11–13, can 
improve treatment compliance14 and may help to reduce the burden on healthcare services. 
However, even home-based ERT administration can cause disruption to a patient’s daily 
activities and usually requires a healthcare professional (HCP) to supervise the infusion. To 
mitigate risk of adverse effects associated with ERT, patients are also frequently administered 
pre-medications with antihistamines and low-dose corticosteroids, which can be an added 
burden to patients. 
Therapeutic options for FD have expanded over the past few years, with the development of 
orally-administered medicines such as Migalastat (Galafold®, Amicus Therapeutics) which has 
received regulatory approval in several countries. In this context, there is a need for 
comprehensive information about the burden of standard-of-care ERT treatments from the 
perspective of both patients and their caregivers and healthcare providers, to enable them to 
make fully informed decisions about the most appropriate treatment strategy.  There is 
currently a paucity of data on the true resource burden associated with use of existing ERT 
and the wider impact of attendance for ERT on HRQoL and work productivity. Although data 
are available about the overall frequency and cost of ERT attendances15,16, there have been 
no published data on the total time and cost involved for patients, caregivers and HCPs. In 
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addition, the impact of receiving ERT on work productivity has been described in market 
research17 and qualitative research18 but has not been formally quantified.  
The present study will address these evidence gaps by generating robust real world data to 
quantify the current burden of ERT for the treatment of FD across four countries. The study 
will utilize a time and motion methodology to measure the total HCP time associated with an 
episode of ERT administration, with patient- and caregiver-reported outcomes including 
HRQoL, wellbeing, work productivity and caregiver strain, to be collected directly from 
patients with FD and their caregivers.  The data may be utilized by Amicus Therapeutics in 
submissions to Health Technology Assessment (HTA) bodies, and will be useful for HCPs to 
inform future treatment decisions and ongoing patient management.  
8. 
Research questions and objectives 
8.1 Research questions  
What is the total HCP time associated with the preparation and administration of a single 
dose of ERT in patients with FD and the patient and caregiver time and costs (out-of-pocket 
expenses) associated with an ERT attendance? What is the impact of FD on patients’ HRQoL, 
wellbeing, levels of fatigue and work productivity? What is the burden of care provision for 
the caregivers of patients with FD and the impact on their work productivity?  
8.2 Hypothesis 
This is a descriptive study and there is no a priori hypothesis to be tested. 
8.3 Primary objective 
To quantify the total time spent by HCPs in the preparation and administration of a single 
dose of ERT (with agalsidase alfa and agalsidase beta) in patients with FD. 
8.4 Secondary objectives 
• To quantify the total patient time, costs (i.e. out of pocket expenses) and work-related 
absence associated with attendances for the administration of a single dose of ERT (with 
agalsidase alfa and agalsidase beta) in patients with FD. 
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• To quantify the total caregiver time, costs (i.e. out of pocket expenses) and work-related 
absence associated with accompanying a patient with FD for the administration of a single 
dose of ERT (with agalsidase alfa or agalsidase beta). 
• To describe patient-reported HRQoL (measured by the 12 Item Short Form Survey [SF-12]), 
wellbeing (measured by the World Health Organization-5 Wellbeing Index [WHO-5]), 
levels of fatigue (measured by a bespoke Fatigue Likert scale) and work productivity 
(measured by the Work Productivity and Activity Index [WPAI] questionnaire) in patients 
with FD treated with ERT. 
• To describe work productivity (measured by the WPAI-CG) and the strain of care provision 
(measured by the Caregiver Strain Index [CSI]) in caregivers of patients with FD treated 
with ERT.  
9. 
Research methods 
This study has been designed and will be conducted according to the requirements of the 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; 
http://www.encepp.eu/index.shtml) and International Society for Pharmacoepidemiology 
(ISPE; 
https://www.pharmacoepi.org/resources/guidelines 08027.cfm) 
guidance, 
as 
appropriate. 
9.1 Study design 
This is an international, non-interventional research study of adult patients with FD and their 
caregivers. The study will comprise a prospective time and motion evaluation and a cross-
sectional evaluation of patient- and caregiver-reported outcomes (including HRQoL, 
wellbeing, levels of fatigue and work-productivity [for patients with FD]; work productivity 
and the strain of care provision [for caregivers]). Patients’ demographic characteristics will be 
collected from hospital medical records. No changes to routine patient management will be 
made for the purposes of any part of this study and there is no requirement for additional 
visits or investigations.  
Separate patient consent will be obtained for the time and motion evaluation and the cross-
sectional evaluation of patient-reported HRQoL, wellbeing, levels of fatigue and work 
productivity; thus, patients who do not wish to complete the study questionnaires will remain 
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eligible for the time and motion study (and vice versa), provided that consent has been 
obtained.  Caregivers will consent to completion of the study questionnaires. 
A prospective design for collection of patient-centred outcomes data was selected since it is 
unlikely that these will be documented in medical records. A prospective design is the only 
appropriate method for collecting time and motion and caregiver-reported outcomes data. 
Based on the rarity of FD, the broad eligibility criteria and the number and types of 
participating centres, the results of this study should be generalisable to the wider patient 
population with FD treated with ERT with agalsidase alfa or agalsidase beta in routine clinical 
practice in the participating countries. 
9.1.1 Prospective time and motion study 
Patients with FD attending the hospital or treatment centre for administration of a single dose 
of ERT (with agalsidase alfa or agalsidase beta) during the prospective recruitment period will 
be observed by an independent researcher or a member of their care team for the duration 
of their episode of care. The observer will record the HCP time associated with all activities 
relating to the preparation and administration of ERT (including the pre-infusion clinical 
assessment and post-administration documentation). It is possible that a single patient may 
present to the hospital or treatment centre for administration of ERT multiple times within 
the recruitment period (when they return for follow-up treatment), but repeated observation 
of the same patient will ideally be capped at two episodes of care per patient, to minimise 
bias from multiple observations of patients with atypical resource use. For countries with 
limited FD patient numbers, a review of episodes of care observed will be completed on an 
ongoing basis.  It may be determined that it is possible to observe three episodes per patient 
in these circumstances, however only two episodes will be observed per patient wherever 
possible.  For patients who are eligible to be observed more than once, initial consent for 
observation of up to three episodes of care will be obtained, and will be confirmed verbally 
by their HCP before the second or third episode of care is observed. 
 
 
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9.1.2 Cross sectional evaluation of patient- and caregiver-reported outcome measures 
Patients with FD and their caregivers will be asked to complete a series of questionnaires, to 
include validated measures of HRQoL, wellbeing and work productivity (for patients); and 
work productivity and the strain of care provision (for caregivers).  
Questionnaires were selected based on their ease of use, short time required for completion 
(in order to minimise the burden on patients), availability in the required languages, and the 
fact that they have been previously validated in a similar context to our study:  
• HRQoL will be assessed using the SF-12 version 2. The SF-12 is a shorter version of the 36 
item Short Form Survey (SF-36) that uses 12 questions to measure functional health and 
wellbeing from the patients’ point of view. It is made up of 8 domains: physical functioning, 
bodily pain, general health, vitality, physical role, role emotional, social functioning and 
mental health19. These 8 domains form 2 subscales: physical component summary and 
mental component summary. The SF-12 was chosen for the present study as it was used 
in a recent registry of patients with FD20 and is less burdensome for patients to complete 
than the longer SF-36. It has a short completion time (approximately 5 minutes) and is 
available in all 4 languages of the study countries. 
• Patients’ general wellbeing will be assessed using the WHO-522. It consists of 5 items and 
the timeframe for responses is based on the previous 2 weeks. The 5 items relate to feeling 
cheerful, calm, active, rested and being interested in life. The WHO-5 was selected to 
assess the impact of FD and its treatment on patients’ well-being. It is quick and easy to 
complete (<5 minutes) and score. 
• The impact of FD on patients’ work lives will be assessed using the WPAI. The WPAI 
consists of 6 items. The WPAI was chosen for the present study as it is quick to complete 
(<5 minutes) and is available in all 4 languages of the countries selected in this study. 
Caregiver-reported outcomes will be evaluated using the following validated questionnaires 
addressing work productivity and the strain of care provision: 
• The impact of caring for a patient with FD on caregivers’ work lives will be assessed using 
the WPAI specific to caregivers (WPAI:CG)24. The WPAI:CG consists of 6 items and was 
chosen for the present study as it is quick to complete (<5 minutes) and is available in all 
4 languages of the study countries. 
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• The strain of providing care for a patient with FD will be assessed using the CSI. The CSI 
consists of 13 items and measures the strain of care provision in five domains (financial, 
physical, psychological, social and personal)23. It takes approximately 5 minutes to 
complete. 
Patients and caregivers will also complete a bespoke questionnaire to evaluate the total time 
associated with attending the hospital or treatment centre for a single ERT administration 
visit, costs (i.e. out of pocket expenses) and time away from work. In addition, patients will 
also be asked about their levels of fatigue using a single-item bespoke Likert scale. Bespoke 
questionnaires will be designed specifically for the purpose of the study.  
It is estimated that it will take approximately 25-30 minutes in total for patients to complete 
their questionnaires (including the second WPAI) and 15-20 minutes for caregivers to 
complete their questionnaires (including the second WPAI:CG). 
Patient questionnaires will be presented in the following order: bespoke Fatigue Likert scale 
(first completion), SF-12, WHO-5, bespoke patient questionnaire (to be started during the ERT 
visit and finished at home), bespoke Fatigue Likert scale second and third completion (to be 
completed on the evening of the ERT administration visit and the next day), WPAI first 
completion (to be completed at home between 1 and 7 days after the ERT infusion [ideally in 
first 2 days]), WPAI second completion (to be completed on the day of the patient’s next ERT 
administration visit). Caregiver questionnaires will be presented in the following order: CSI, 
bespoke caregiver questionnaire (to be started during the ERT administration visit and 
finished at home), WPAI:CG first completion (to be completed at home between 1 and 7 days 
after the ERT infusion), WPAI:CG second completion (to be completed on the day of the 
patient’s next ERT administration visit).  
The full schedule for completion of the study questionnaires for patients and caregivers is 
provided in Table 3 below. 
 
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Table 3. Timeline of completion and list of questionnaires administered to patients and 
caregivers 
Participant 
group 
Timeline of questionnaire completion 
During ERT infusion 
visit 
Evening of ERT 
infusion 
1-7 days after 
ERT infusion 
Day of next ERT 
infusion 
(~15 days after 
previous 
infusion)  
Patients 
with FD 
• Bespoke Fatigue 
Likert scale 
• SF-12 
• WHO-5 
• Bespoke patient 
questionnaire (to 
be started during 
ERT infusion visit 
and finished at 
home) 
  
• Bespoke 
Fatigue 
Likert scale 
On Day 1 after 
ERT infusion:  
• Bespoke 
Fatigue 
Likert scale 
Any day 1-7 
after ERT 
infusion:  
• WPAI 
• WPAI 
Caregivers 
of patients  
with FD 
• CSI  
• Bespoke caregiver 
questionnaire (to 
be started during 
ERT infusion visit 
and finished at 
home) 
 - 
Any day 1-7 
after ERT 
infusion: 
• WPAI:CG 
• WPAI:CG 
SF-12: Short Form-12 questions, WHO-5: World Health Organisation 5 questions, WPAI: Work 
Productivity and Activity Impairment, CG: Caregiver.  
 
9.2 Setting 
Patients with FD who are receiving ERT and their caregivers will be identified and recruited 
from approximately 8-12 specialist centres across four countries (Taiwan, Turkey, Brazil and 
Japan). The number of sites needed to achieve the required sample size may vary between 
the participating countries; this will be determined by the study management company (in 
consultation with Amicus Therapeutics), depending on the number and size of potentially 
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eligible study sites in each country. It is anticipated that 2-3 sites will be required in each 
country. 
The participating centres will be specialist hospitals or treatment centres with experience of 
treating patients with FD with ERT (agalsidase alfa or agalsidase beta or both), interest in 
taking part in the study and likely availability of the required number of eligible patients/ERT 
episodes during the recruitment period.  
In some of the participating countries, the preparation and administration of ERT takes place 
exclusively in the hospital setting; in these countries the study will be conducted solely within 
the hospitals (or infusion centres affiliated to the hospitals) from which the patients and 
caregivers are recruited. In other countries, ERT preparation and administration can take 
place in both hospitals and community healthcare centres (i.e. primary care treatment 
facilities). In these countries, patients who receive ERT in primary care (and their caregivers) 
will still be identified and recruited from their main (specialist) hospital, but the time and 
motion component of the study (observation of ERT preparation and administration) and 
distribution of patient- and caregiver- reported outcome measures and questionnaires will 
take place at their community healthcare centre (from which the relevant approvals to 
conduct the study will also be obtained). In some cases, patients may attend their community 
healthcare centre for the ERT infusion to be set up, and return home to start/deliver the 
infusion; these patients (and their caregivers) will still be included in the study, and the total 
HCP/patient and caregiver time recorded as for other episodes while the patient attends the 
community healthcare centre.  Patients will capture the infusion time themselves by 
completing the bespoke questionnaire provided.                                                                                                          
It is not routine practice in the countries of study for ERT preparation and administration to 
take place exclusively in the home setting, or for HCPs to attend the patient’s home to assist 
with the infusion, although this may occur in exceptional circumstances (for example, if the 
patient themselves is a trained HCP). For this reason, patients who prepare and administer 
their ERT exclusively in the home setting will be excluded from the study, as resource use is 
likely to be atypical.     
 
 
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9.3 Study time periods 
It is anticipated that the prospective recruitment / data collection period for this study will 
be approximately 4-5 months, starting from the date on which the relevant approvals to 
conduct the study are in place. Ideally, a maximum of two episodes of care per patient during 
the data collection period will be included for the time and motion evaluation (except in 
exceptional cases where it is determined that it is required to observe three episodes per 
patient due to a limited number of available patients/episodes for observation). Patients with 
FD and their caregivers will be asked to complete the study questionnaires once during the 
data collection period, when the patient attends the hospital or treatment centre for 
administration of ERT; the exception is the work productivity questionnaire, which will be 
completed on two occasions and the bespoke Fatigue Likert scale, which will be completed 
on three occasions (as described above). Separate patient consents will be obtained for the 
time and motion evaluation and cross-sectional questionnaire completion so patients will 
have the option to take part in only one or both parts of the study, according to their 
preference. 
9.4 Study population 
The source population for this study is adult patients with FD, recruited from four countries 
(Taiwan, Turkey, Brazil and Japan) who attend the participating hospitals, treatment centres 
or community healthcare facilities for administration of ERT (as part of their routine 
treatment) during the data collection period, and their caregivers. It is anticipated that 
approximately 60 episodes of care (30 with agalsidase alfa and 30 with agalsidase beta) per 
country, ideally up to a maximum of two episodes per patient (except in exceptional cases 
where it is determined that it is required to observe three episodes per patient due to a 
limited number of available patients/episodes for observation), will be included in the time 
and motion study, and approximately 30 sets of patient questionnaires and 5 sets of caregiver 
questionnaires per country (in total) will be completed.   
Patients and caregivers fulfilling the following criteria will be eligible for inclusion in the study:  
9.4.1 Selection criteria for patients 
Patient inclusion criteria  
• Patients aged 18 years old or over at time of consent. 
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• Patients with a documented diagnosis of FD. 
• Patients who have received ≥4 doses of ERT (with agalsidase alfa or agalsidase beta) for 
the treatment of FD. 
• Patients who present to the participating hospital(s) or treatment centre(s) for 
administration of a dose of ERT (as part of their routine treatment) during the data 
collection period. 
Patients who meet any of the following criteria will be excluded: 
• Patients aged <18 years at time of consent 
• Patients who are unable or unwilling to give consent for study participation. 
• Patients for whom ERT preparation and administration takes place exclusively in the home 
setting. 
• For the time and motion evaluation: Patients whose ERT is administered by a HCP who 
does not consent to be observed. 
9.4.2 Selection criteria for caregivers 
Caregiver inclusion criteria: 
• Aged 18 years of age or over at time of consent. 
• Self-identifies as a caregiver of a patient with FD for whom written informed consent has 
been obtained for inclusion in the study.   
Caregivers who meet any of the following criteria will be excluded: 
• Caregiver (and/or the patient with FD whom they support or care for) is unable or 
unwilling to give consent for study participation. 
9.4.3 Selection criteria for staff (for time and motion study) 
Staff inclusion criteria (for time and motion study): 
• Members of the whole care team responsible for preparing and administering agalsidase 
alfa and agalsidase beta to patients with FD.  
• Staff who have given written consent to be observed during the preparation and provision 
of care. 
 
 
 
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9.5 Patient identification, sampling and recruitment 
Adult patients with FD who are receiving treatment with ERT will be identified from local 
databases and pharmacy records by members of the whole care team at each centre and 
assessed for eligibility in line with the inclusion criteria. Patients will be approached by a 
member of their care team, given information about the study and invited to consent to 
participate. Patients may be approached in advance of their next scheduled attendance for 
ERT administration (by telephone and/or post) or in person, at a routine hospital visit. If 
patients do not wish to complete the study questionnaires they are still eligible for the time 
and motion study (and vice versa), provided that consent for the relevant component of the 
study has been obtained. For patients who are eligible to be observed more than once (for 
the time and motion study), initial consent for observation of up to three episodes of care will 
be obtained, and will be confirmed verbally by their HCP before the second and third episode 
of care.  Each patient will only be asked to complete one set of questionnaires (with the 
exception of the work productivity questionnaire, which will be completed twice and the 
bespoke Fatigue Likert scale, which will be completed three times), even if they contribute 
more than one episode of care to the time and motion study. 
Caregivers will only be invited to participate in the study if the patient whom they care for 
also consents to study participation. Caregivers will be approached for consent when they 
attend the hospital or treatment centre with the patient for their ERT administration visit. 
Consecutive eligible patients (and their caregivers) presenting at the participating centres 
during the prospective recruitment period will be included in the study until the required 
sample size is reached. It is anticipated that patient and caregiver recruitment will take place 
over a 4-5 month period, starting from the date on which the relevant approvals needed to 
conduct the study are in place.   
Prior to commencement of data collection, HCPs at the participating centres (and community 
healthcare facilities, where relevant) who are involved in the administration of ERT will be 
identified and asked to provide consent to be observed in their provision of care. Consent 
from HCPs will be confirmed by the observer verbally before each episode of care.   
 
 
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9.6 Variables 
Study endpoints will be reported using descriptive statistics of distribution, central tendency 
and dispersion as appropriate for the data collected, as outlined in Section 0. 
The study endpoints and dataset required to address the study objectives are summarised in 
Table 4 (please note that the response categories listed below are indicative only; the final 
list to be collected will be specified in the case report form (CRF)/electronic CRF (eCRF) and 
associated guidelines).  
Table 4. Endpoints and dataset required to address the study objectives 
Endpoint to address the primary objective 
Dataset required to address the primary 
objective 
Endpoint(s) and dataset required to address the primary objective: To quantify the total 
time spent by HCPs in the preparation and administration of a single dose of ERT (with 
agalsidase alfa and agalsidase beta) in patients with FD. 
Primary endpoint: Summary measures of the 
total time spent by HCPs in the preparation and 
administration of a single dose of ERT in 
patients with FD; stratified by country and by 
ERT product (agalsidase alfa or agalsidase 
beta).   
 
Secondary endpoints:  
 
• Summary measures of the time spent by 
HCPs on the following tasks associated with 
the preparation and administration of a 
single dose of ERT (with agalsidase alfa or 
agalsidase beta) in patients with FD: 
o Pre-administration 
patient 
consultation. 
For each episode of care: 
• Name/s of observer 
• Patient and staff ID 
• Episode date 
• Episode setting (hospital / infusion 
centre / primary healthcare centre / 
primary 
healthcare 
centre 
(preparation and set-up) with home 
infusion) / other (specify) 
• ERT product administered: agalsidase 
alfa  (Replagal®, Shire or biosimilar) or 
agalsidase beta (Fabrazyme®, Sanofi 
Genzyme or biosimilar) 
• ERT dose administered. 
• Pre-medications administered 
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o Infusion 
(and 
pre-medication) 
preparation activities. 
o Administration of ERT (and pre-
medications). 
o Monitoring of patient during and 
after administration. 
o Completion 
of 
clinical 
documentation. 
o Any 
other 
ERT-administration 
related activities.  
• Distribution of the roles of HCP (physician / 
nurse / nurse assistant or healthcare 
assistant / pharmacist / pharmacy assistant 
/ other) involved in each task.  
• Summary measures of the ERT dose 
administered. 
 
• Activities 
associated 
with 
the 
preparation and administration of  
ERT: 
• Pre-administration 
patient 
consultation: 
o Time patient arrived in clinic 
room. 
o Time patient left clinic room.  
o Start and end time of patient 
consultation with HCP for pre-
treatment assessment. 
o Start 
and 
end 
time 
of 
prescription 
writing 
(if 
additional 
to 
consultation 
time with patient). 
o Start and end time of pre-
administration 
clinical 
documentation (if additional 
to consultation time with 
patient). 
o Role 
of 
HCP(s) 
involved 
(physician / nurse / nurse 
assistant 
or 
healthcare 
assistant / other [specify]). 
• Infusion 
(and 
pre-medication) 
preparation activities: 
o Start and end time of infusion 
(and 
pre-medication) 
preparation activities (note: 
the following activities [as 
appropriate] will be included 
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in the total time, but the time 
for each separate activity will 
not 
be 
recorded]: 
pre-
dispensing 
prescription 
review, 
label 
generation, 
collation of items prior to 
assembly, 
assembly 
of 
item/drug 
reconstitution, 
labelling 
of 
containers, 
accuracy check, prescription 
delivery). 
o Role 
of 
HCP(s) 
involved 
(physician / nurse / nurse 
assistant 
or 
healthcare 
assistant 
/ 
pharmacist 
/ 
pharmacy assistant / other 
[specify]). 
• ERT 
(and 
pre-medication) 
administration: 
o Time patient arrived in clinic 
for ERT administration 
o Time 
patient 
left 
clinic 
following ERT administration 
o Start and end time of pre-
medication administration. 
o Start and end time of ERT 
infusion. 
o Start and end time of HCP 
activity for administration of 
IV agalsidase alfa or agalsidase 
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beta (including administration 
of pre-medications). 
o Start and end time of HCP 
activity for patient monitoring 
during agalsidase alfa or 
agalsidase beta infusion 
o Role 
of 
HCP(s) 
involved 
(physician / nurse / nurse 
assistant 
or 
healthcare 
assistant 
/ 
pharmacist 
/ 
pharmacy assistant / other 
[specify]). 
• Post-administration assessment and 
documentation: 
o Start and end time of HCP 
activity for post-treatment 
patient 
assessment 
/ 
monitoring. 
o Start and end time of HCP 
activity for completion of 
clinical documentation. 
o Role 
of 
HCP(s) 
involved 
(physician / nurse / nurse 
assistant 
or 
healthcare 
assistant 
/ 
pharmacist 
/ 
pharmacy assistant / other 
[specify]). 
• Other 
ERT-administration 
related 
activities 
o Start and end time of HCP 
activity for any other ERT-
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administration 
related 
activities (specify). 
o Role 
of 
HCP(s) 
involved 
(physician / nurse / nurse 
assistant 
or 
healthcare 
assistant 
/ 
pharmacist 
/ 
pharmacy assistant / other 
[specify]). 
Endpoints to address the secondary objectives Dataset 
required 
to 
address 
the 
secondary objectives 
Secondary objective 1: To quantify the total patient time, costs (i.e. out-of-pocket 
expenses) and work-related absence associated with attendances for the administration 
of a single dose of ERT (with agalsidase alfa or agalsidase beta) in patients with FD. 
• Summary measures of the total patient 
time associated with attendance for the 
administration of a single dose of ERT (with 
agalsidase alfa or agalsidase beta) in 
patients with FD. To include: 
• Time spent travelling to and from the 
hospital or treatment centre 
• Time spent collecting ERT from pharmacy 
(where relevant) 
• Time from arrival in hospital/treatment 
centre to departure 
• Time from arrival in hospital/treatment 
centre to start of ERT infusion 
• In addition, if the patient started/delivered 
their ERT infusion at home following set-up 
at a primary healthcare centre, the 
Patient responses to the bespoke study 
questionnaire: 
• Patient ID 
• Date of episode 
• Patient 
employment 
status 
(employed full time / employed part 
time / unemployed / retired / student 
/ home-maker) 
• Were they accompanied to the 
hospital or treatment centre (by a 
relative or caregiver) or did they 
attend alone (accompanied / alone)  
• Time left home/work to travel to 
hospital or treatment centre 
• Time arrived at hospital or treatment 
centre 
• Time of start of ERT infusion. 
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following will also be included in the total 
patient time: 
• Duration of ERT infusion and any home-
based post-administration activities. 
• Time spent travelling to and from 
treatment centre after ERT infusion (only if 
patient returned to treatment centre after 
ERT infusion) 
• Time spent at treatment centre after ERT 
infusion. 
• Summary measures of the total cost to 
patients (i.e. out-of-pocket expenses) 
associated with attendance for the 
administration of a single dose of ERT (to 
include the costs of travel / parking / 
subsistence / other costs). 
• 
Distribution of patient employment status 
and whether the patient attended the ERT 
administration visit accompanied by a 
relative/caregiver or alone. 
• 
Proportion of patients with work absence 
due to attendance for this ERT episode and 
number of paid / unpaid hours absent.  
• Time left hospital or treatment centre 
to travel back to home/work. 
• Time arrived back at home/work. 
Whether patient returned to work on the 
day of the infusion or the following day.  
If the patient started their ERT infusion at 
home following set-up at a primary 
healthcare centre, the following will also 
be collected:  
• Start and end time of ERT infusion 
• Start and end time of any post-
administration activities.  
• Time left home/work to return to 
hospital or treatment centre (if 
relevant) 
• Time arrived back at hospital or 
treatment centre (if relevant) 
• Time left hospital or treatment centre 
to travel back to home/work 
• Time arrived back at home/work 
• Did patient take any time off work to 
attend this ERT episode? If yes, 
number of paid / unpaid hours absent 
from work. 
• Number of hours worked during ERT 
infusion (if relevant).  
• Costs (i.e. out-of-pocket expenses) 
incurred by the patient that were 
directly 
related 
to 
this 
ERT 
administration episode (to include 
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costs of travel / parking / subsistence 
/ any other costs). 
Secondary objective 2: To quantify the total caregiver time costs (i.e. out-of-pocket 
expenses) and work-related absence associated with accompanying a patient with FD for 
the administration of a single dose of ERT (with agalsidase alfa or agalsidase beta). 
• Summary measures of the total caregiver 
time associated with accompanying a 
patient with FD for the administration of a 
single dose of ERT (with agalsidase alfa or 
agalsidase beta).  To include: 
• Time spent travelling to and from the 
hospital or treatment centre 
• Time spent collecting ERT from pharmacy 
(where relevant) 
• Time from arrival in hospital/treatment 
centre to departure 
• Time from arrival in hospital/treatment 
centre to start of patient’s ERT infusion 
• In addition, if the patient started/delivered 
their ERT infusion at home following set-up 
at a primary healthcare centre, the 
following will also be included in the total 
caregiver time (if the caregiver was 
involved in the activity): 
• Duration of ERT infusion and any home-
based post-administration activities. 
• Time spent travelling to and from 
treatment centre after ERT infusion (only if 
patient returned to treatment centre after 
ERT infusion and was accompanied by a 
caregiver) 
Caregiver responses to the bespoke 
study questionnaire: 
• Caregiver ID and patient ID 
• Date of episode 
• Caregiver sex (male / female) 
• Caregiver age category (<20 years / 
20<30 years, 30<40 years, 40<50 
years, 50<60 years, 60<70 years, 
70<80 years, 80 years or over) 
• Does the caregiver also have FD?  
• Caregiver 
employment 
status 
(employed full time / employed part 
time / unemployed / self-employed / 
retired / student / home-maker) 
• Caregiver relationship to patient 
(parent / spouse or partner / son or 
daughter / other relative / friend or 
neighbour) 
• Type and frequency of care or 
support provided by the  caregiver to 
the patient with FD 
• Time left home/work to travel to 
hospital or treatment centre 
• Time arrived at hospital or treatment 
centre 
• Time of start of ERT infusion  
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• Time spent at treatment centre after ERT 
infusion. 
• Summary measures of the total cost to 
caregivers (i.e. out-of-pocket expenses) 
associated with accompanying a patient 
with FD for the administration of a single 
dose of ERT (to include the costs of travel / 
parking / subsistence / other costs). 
• Distribution 
of 
caregiver 
age, 
sex, 
employment status, relationship to the 
patient with FD, type/frequency of support 
provided and proportion with FD. 
• 
Proportion of caregivers with work 
absence due to accompanying the patient 
for this ERT episode and number of paid / 
unpaid hours absent.  
• Time left hospital or treatment centre 
to travel back to home/work 
• Time arrived back at home/work. 
 
If the patient started their ERT infusion at 
home following set-up at a primary 
healthcare centre, the following will also 
be collected (if the caregiver was involved 
in the activity):  
• Start and end time of ERT infusion 
• Start and end time of any post-
administration activities.  
• Time left home/work to return to 
hospital or treatment centre (if 
relevant and if accompanied by 
caregiver) 
• Time arrived back at hospital or 
treatment centre (if relevant) 
• Time left hospital or treatment centre 
to travel back to home/work 
• Time arrived back at home/work 
• Did caregiver take any time off work 
to attend this ERT episode? If yes, 
number of paid / unpaid hours absent 
from work. 
• Number of hours worked during ERT 
infusion (if relevant).  
• Costs (i.e. out-of-pocket expenses) 
incurred by the caregiver that were 
directly related to accompanying the 
patient for this ERT administration 
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episode (to include costs of travel / 
parking / subsistence / any other 
costs). 
Secondary objective 3: To describe patient-reported HRQoL (measured by the SF-12), 
wellbeing (measured by the WHO-5), levels of fatigue (measured by the bespoke Fatigue 
Likert scale) and work productivity (measured by the WPAI) in patients with FD treated 
with ERT (with agalsidase alfa or agalsidase beta). 
Summary measures of patients’: 
• HRQoL (SF-12 scores / responses). 
• General wellbeing (WHO-5 scores 
/ 
responses). 
• Level of fatigue (bespoke Fatigue Likert 
scale). 
• Levels of work impairment (WPAI scores / 
responses). 
 
Questionnaire scores and/or item responses 
will be reported using summary statistics, as 
appropriate to the questionnaire and in 
accordance with the licensed scoring manual / 
instructions for use. 
• Patient SF-12, WHO-5, Fatigue Likert 
scale and WPAI responses and dates 
of completion. For the bespoke 
Fatigue Likert scale, times (hours and 
minutes) of completion will also be 
recorded.  
 
Secondary objective 4: To describe work productivity (measured by the WPAI:CG) and the 
strain of care provision (measured by the CSI) in caregivers of patients with FD treated 
with ERT. 
Summary measures of caregivers’: 
• Levels of work impairment (WPAI:CG 
scores / responses). 
• Levels of strain of providing care for a 
patient with FD (CSI scores / responses). 
 
• Caregiver WPAI:CG and CSI responses 
and date of completion. 
 
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Questionnaire scores and/or item responses 
will be reported using summary statistics, as 
appropriate to the questionnaire and in 
accordance with the licensed scoring manual / 
instructions for use. 
Patients’ demographic and clinical characteristics (all patients) 
Summary measures of (at date of consent, 
unless specified): 
• Sex. 
• Age at onset of first symptoms, at FD 
diagnosis and at date of consent. 
• Duration of ERT treatment. 
• ERT treatment. 
• FD phenotype (organs involved). 
• FD mutation ((if known).   
• Severity of FD (to be determined using the 
specified baseline information]). 
• Any other relatives (with whom the patient 
lives) with FD. 
• Number and type (agalsidase alfa / 
agalsidase beta) of ERT infusions received 
in the year prior to date of enrolment. 
• Sex (male / female). 
• Date of consent. 
• Age at consent. 
• Age at onset of first symptoms. 
• Date of FD diagnosis. 
• ERT start date. 
• ERT treatment under observation 
(agalsidase alfa / agalsidase beta). 
• Number of ERT infusions received in 
the year prior to date of enrolment, 
by type of treatment (algasidase alfa, 
algasidase beta).  
• FD 
phenotype 
(organ 
involvement/complications), 
to 
include any current or prior history of: 
hypohidrosis, 
neuropathic 
pain 
(and/or acroparasthesia and/or acute 
pain 
crises), 
cornea 
verticillata, 
angiokeratomas, hearing impairment 
(including deafness and/or tinnitus), 
cardiac events (including rhythm 
and/or 
conduction 
disturbances, 
hypertrophic cardiomyopathy or left 
ventricular mass index [LVMi] above 
normal range, myocardial infarction 
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[MI], unstable angina, congestive 
heart failure, major cardiac medical 
procedures), renal events (including 
reduced 
estimated 
glomerular 
filtration 
rate 
[eGFR], 
abnormal 
albumin 
creatinine 
ratio 
[ACR], 
proteinuria or albuminuria, dialysis, 
kidney transplant), central nervous 
system (CNS) involvement (including 
brain magnetic resonance imaging 
[MRI] changes [white matter lesions], 
transient ischaemic attack [TIA] or 
stroke), FD-related gastrointestinal 
[GI] symptoms, plasma lyso-Gb3 
levels above normal, low white blood 
cells 
(WBC) 
alpha-galactosidase, 
other: specify) 
• eGFR at enrolment (closest 
measurement prior and preferably 
within 12 months); date and 
measurement. 
• Urine protein levels at enrolment 
(closest measurement prior); date 
and measurement. 
• WBC alpha-galactosidase (closest 
prior to enrolment); date and 
measurement 
• LVMi 
at 
enrolment 
(closest 
measurement prior and preferably 
within 
12 
months); 
date 
and 
measurement. 
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• FD mutation (name of mutation, if 
known, including: e.g. A143T)  
• Severity of FD (mild / moderate / 
severe), to be determined using the 
following baseline information:  
o Type of FD (classical / non 
classical). If type is 
unavailable, it will be inferred 
from the information 
collected below*.  
▪ Number of organs 
involved (per medical 
history, as detailed 
above). 
▪ eGFR at enrolment. 
▪ Urine protein levels at 
enrolment. 
▪ LVMi at enrolment. 
▪ WBC alpha-
galactosidase at 
enrolment. 
• Do any other relatives with whom the 
patient lives have FD (Yes / No / Not 
known). 
 
*FD will be defined as classical if (1) multi-
organ disease at baseline (≥ 2 organs) as 
determined by medical history or 
baseline values for eGFR, urine protein, 
LVMi, AND (2) white blood cells alpha-
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galactosidase below cut-off at baseline 
(≤3% wild-type).  
 
 
 
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9.7 Data source 
Patients’ demographic and clinical data will be sourced from patients’ medical records and 
other systems within the main (specialist) participating FD centres.   
For the time and motion component of the study, prospective data relating to HCP time 
associated with the preparation and administration of a single dose of ERT will be captured 
by direct observation of HCPs during the episode of care by an independent external observer 
or a member of the patients’ care team.  
Patient- and caregiver-reported outcomes will be reported directly by patients and their 
caregivers using anonymised-coded paper-based questionnaires. Questionnaires will be given 
to consenting patients and caregivers by members of the patients’ whole care team during an 
ERT administration visit. If the ERT infusion takes place in a hospital or treatment centre, it is 
anticipated that the validated questionnaires (with the exception of the first work 
productivity questionnaire) will be completed by the patient or caregiver during the ERT 
infusion and returned to centre staff in sealed envelopes for forwarding to the study 
management company, before they leave the clinic. The first work productivity questionnaire 
will be completed by the patient or caregiver at home between 1 and 7 days after date of the 
patient’s ERT infusion.  The bespoke questionnaire (which requires the patient or caregiver to 
document the time of leaving the clinic and the time to return to home/work) will also be 
completed by the patient or caregiver after leaving the clinic and returned to the centre 
(together with the first work productivity questionnaire) at a later date, either in person (at 
the patient’s next ERT administration attendance) or by post (using a pre-paid envelope). 
Alternatively, their responses to the first work productivity questionnaire, the bespoke 
questionnaire and the bespoke Fatigue Likert scale may be collected over the telephone 
during call with a member of the patient’s care team, or following a reminder call from a 
member of the patient’s care team to fill in the questionnaires.  If part of the episode of care 
takes place in the patient’s home, it is likely that all study questionnaires will be completed 
by the patient or caregiver at home and returned to the centre as described above.  
 
 
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9.8 Study size 
This study aims to recruit sufficient patients to record 30 episodes per treatment per country. 
Given this, the number of patients recruited will range from 15 to 30 per treatment per 
country. To evaluate the value of the sample estimates of the population that this sample size 
will allow for, it will be assumed pessimistically that each patient will have one measurement; 
the estimates once the study is carried out will therefore have higher precision than 
calculated below. 
The anticipated length of time for pre and post-administration activities and infusion for each 
treatment utilised estimates from the research of Guest et al.17 alongside clinical opinion 
sourced from sites in the countries of study; it was estimated that pre-administration 
processes would always take between 10-30 minutes, post-administration processes would 
take between 15-30 minutes, infusion of agalsidase alfa takes between 40 to 60 minutes and 
infusion of agalsidase beta would take between 90 to 180 minutes. To anticipate the precision 
of estimates given the sample size above, it was estimated that these times would follow a 
normal distribution within these ranges (as a result, the mean could be estimated by taking 
the middle value of the range and the standard deviation roughly approximated accordingly). 
It is important to account for the fact that Fabry disease is rare and that the sample collected 
will represent a large proportion of the total population with disease. For instance, in the US, 
it was estimated that there were only approximately 7700 patients in total out of a population 
of about 323 million in 2016, which suggests that only 0.0024% have the disease. The 
estimated number of Fabry disease patients in other countries can be calculated from the 
prevalence of the disease in the US, by multiplying the expected proportion of the population 
with the disease (assuming that the prevalence is similar in the US to other countries) with 
the estimated total population (Brazil, Japan, Taiwan and Turkey therefore could have an 
estimated patient population of about 5015, 3033, 573 and 1934 patients respectively based 
on estimates of total population of 210 million, 127 million, 24 million and 81 million patients 
respectively24). Accounting for this, the estimated precision of estimates of time at different 
sample sizes for the largest and smallest countries in the study by population can be seen in 
the table below. 
 
 
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Table 5. Sample size estimations 
Cohort 
Activity 
/ 
Estimate 
95% confidence interval at different sample sizes 
15 patients 20 patients 25 patients 30 patients 
Brazil 
Pre-Admin 
activity 
Mean: 
20 
minutes 
 17m 14 -
22m 46 
 17m 40 -
22m 20 
 17m 56 -
22m 04 
18m 08 -
21m 52 
Post-Admin 
activity 
Mean: 22 mins 
30 
20m 26 – 
24m 34 
 20m 45 – 
24m 15 
 20m 57 – 
24m 03 
21m 06 – 
23m 53 
ERT Alfa 
Mean: 
50 
minutes 
47m 14 – 
52m 46 
47m 40 – 
52m 20 
47m 56 – 
52m 04 
48m 08 – 
51m 52 
ERT Beta 
Mean: 
135 
minutes 
122m 33 – 
147m 27 
124m 29 – 
145m 31 
125m 44 – 
144m 16 
126m 37 – 
143m 23 
Overall Alfa 
Mean: 92 mins 
30 
84m 54 – 
100m 06 
86m 05 – 
98m 55 
86m 50 – 
98m 10 
87m 23 – 
97m 37 
Overall Beta 
Mean: 177 mins 
30 
 160m 13 – 
194m 47 
 162m 54 – 
192m 06 
164m 38 – 
190m 22 
165m 52 – 
189m 08 
Taiwan 
Pre-Admin 
activity 
17m 16 – 
22m 44 
17m 42 -
22m 18 
 17m 59 -
22m 01 
18m 08 -
21m 52 
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Mean: 
20 
minutes 
Post-Admin 
activity 
Mean: 22 mins 
30 
20m 27 – 
24m 33 
20m 46 – 
24m 14 
20m 59 – 
24m 01 
21m 06 – 
23m 54 
ERT Alfa 
Mean: 
50 
minutes 
47m 16 – 
52m 44 
47m 42 – 
52m 18 
47m 59 – 
52m 01 
48m 08 – 
51m 52 
ERT Beta 
Mean: 
135 
minutes 
122m 42 – 
147m 18 
124m 39 – 
145m 21 
125m 55 – 
144m 05 
126m 37 – 
143m 23 
Overall Alfa 
Mean: 92 mins 
30 
84m 59 – 
100m 01 
86m 10 – 
98m 50 
86m 57 – 
98m 03 
87m 23 – 
97m 37 
Overall Beta 
Mean: 177 mins 
30 
160m 24 – 
194m 36 
163m 07 – 
191m 53 
164m 52 – 
190m 08 
165m 52 – 
189m 08 
 
The higher the number of patients available to sample from the more precise the estimates 
of time taken for each activity will be, yet even at a worse-case scenario, 95% confidence 
intervals should be sufficient to describe the burden associated with ERT administration. 
Estimates taken from countries where the sample size represents a higher proportion of the 
total population with the disease, such as Taiwan will also be slightly more precise. 
Therefore, the target sample size for the time and motion evaluation undertaken as part of 
this study is 240 ERT episodes, including 60 ERT episodes (30 for agalsidase alfa and 30 for 
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agalsidase beta) in each participating country. Ideally, a maximum of two ERT administration 
episodes will initially be observed per patient (except in exceptional cases where it is 
determined that it is required to observe three episodes per patient due to a limited number 
of available patients/episodes for observation), and at least 30 patients are expected to be 
enrolled in each country.  For countries with limited FD patient numbers, a review of episodes 
of care observed will be completed on an ongoing basis.  It may be determined that it is 
possible to observe three episodes per patient in these circumstances, however only two 
episodes will be observed per patient wherever possible.    
For the questionnaire evaluation, approximately 120 patients and 20 caregivers will be 
expected to fill questionnaire sets (approximately 30 patients’ and 5 caregivers’ 
questionnaire sets per county). 
 
9.9 Data management 
9.9.1 Data collection 
Patient demographic data will be collected using an anonymised-coded standardised eCRF 
designed specifically for the study. Patients will be identified in all study records by a unique 
study code to link multiple study records for each participant (if applicable) and preserve 
patient confidentiality. Data will be collected by members of the care team at each centre or 
external researchers (to be confirmed in each country prior to study commencement) using 
an electronic data capture (EDC) system through eCRFs. 
For the prospective time and motion component of the study, trained external observers who 
are independent of the care process will attend the hospital or treatment centre and observe 
consenting patients’ episodes of care. Alternatively, episodes of care may be observed by 
trained members of the patients’ care team at each site, who are not performing the tasks 
that are being observed. Data will be collected about the procedures involved in the 
preparation and administration of ERT with agalsidase alfa or agalsidase beta, the job roles of 
HCPs involved and the time taken to complete the activities (start and stop time for each 
activity); this will be measured from the start of the first activity related to ERT preparation / 
administration (e.g. start of the pre-infusion clinical assessment) until completion of the last 
activity related to ERT preparation / administration (e.g. completion of the post-infusion 
documentation). The time taken to prepare and dispense the relevant medication will also be 
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collected by observation of pharmacy or nursing staff (as appropriate). Data for the time and 
motion component of the study will be collected using an anonymised-coded standardised 
paper-based CRF designed specifically for the study. The anonymised-coded data will then be 
transcribed into the eCRF by an appropriate member of staff.  
Data management for eCRFs will be carried out using MACRO™, a data management system 
which has a secure web-based data entry interface and is fully validated and compliant with 
Food and Drug Administration (FDA) Information Governance standard 21 Code of Federal 
Regulations (CFR) Part 11. The MACRO™ system has restricted access, role-based permissions 
for data entry management and analysis and maintains an audit trail of all changes to data 
and activity in the system in line with 21 CFR Part 11. Members of the whole care team and 
external researchers will be trained in data entry into the eCRFs by study management staff 
from Open Health. Entry to MACRO™ will be restricted (by password protection) to only those 
members of staff directly involved with the study. 
Consenting patients and caregivers will be given the relevant paper-based patient- and 
caregiver-reported outcome measures to complete either during the visit to the hospital or 
treatment centre for administration of ERT or at home after leaving the clinic (as described 
above).  Completed questionnaires will be handed back or posted (using a pre-paid envelope) 
to the hospital or treatment centre staff or, alternatively, responses to the questionnaires 
completed by patients and caregivers after leaving the clinic (bespoke questionnaire, second 
and third bespoke fatigue Likert scale and first WPAI questionnaire) may be collected over 
the telephone during a call with a member of the patient’s care team.  The hospital or 
treatment centre staff will forward the completed questionnaires to the study management 
company for entry into a bespoke study database in Microsoft Excel™. Entry to the study 
database will be restricted (by password protection) to only those members of staff directly 
involved with the study.  
Data will be prepared for analysis using R statistical software version 3.4.1, Stata™ (StataCorp 
LLC) version 14 and/or Microsoft Excel™. Data management and handling of data will be 
conducted according to the study-specific data management plan (DMP). 
9.9.2 Data analysis  
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A detailed description of study analysis and reporting will be provided in a separate statistical 
analysis plan (SAP) to be finalised before data collection is completed. Analyses will be carried 
out by Open Health using R statistical software, Stata™ (StataCorp LLC) version 14 and 
Microsoft Excel™. Data will be analysed separately for each participating country and by ERT 
treatment (agalsidase alfa /agalsidase beta). 
The planned statistical analyses are summarised below.  
This study is designed to be descriptive in nature; there is no a priori hypothesis to be tested 
and therefore no comparisons between patient subgroups or treatments will be made. 
Distributions and descriptive statistics of central tendency (medians and arithmetic or 
geometric means) and dispersion (standard deviation [SD], interquartile range [IQR], range) 
will be presented for quantitative variables. Categorical variables will be described with 
frequencies and percentages; where appropriate, distributions, modes, medians, IQR and 
range will be reported. Where appropriate, 95% confidence intervals (95% CI) will also be 
presented for means and estimates of proportions. Ordinal variables will be evaluated using 
either frequencies and percentages or medians and IQR or both depending on the number of 
possible values for the variable. 
Analysis for validated instruments will adhere to the licensed scoring manual. Item and 
domain scores (if relevant) will be presented. 
All percentages will be reported to the nearest whole number; therefore, in reporting study 
results in tables, figures and associated text, percentages may not add up to 100% due to 
rounding. For total group/subgroup sizes of less than 10, percentages will not be reported, 
except under exceptional circumstances. Consideration will be given during data analysis as 
to whether reporting any of the planned analyses may identify individuals from combinations 
of variables occurring in very small groups; to preserve participant anonymity such results 
may be suppressed in the study report and any materials intended for publication. 
9.9.3 Missing data 
Where dates are ambiguous because of missing day and/or months, standard imputation will 
be applied: where day is missing the 15th of the month will be assumed; where both day and 
month are missing the 1st July will be assumed.  
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For other missing data, the affected analyses will be conducted using only the results of those 
patients/episodes with data available and the number included in each analysis will be stated. 
The number of patients or caregivers with data missing will be reported for each study 
variable. 
9.9.4 Subgroup and sensitivity analyses 
The primary endpoint (and secondary endpoint, if numbers are sufficient) analyses will be 
conducted overall and repeated with stratification of the sample by country and by type of 
ERT (agalsidase alfa / agalsidase beta). If numbers are sufficient, analyses may be conducted 
by severity of FD (mild / moderate / severe [to be determined using the patients’ baseline 
information, as described above]). 
No sensitivity analyses are planned. 
9.9.5 Interim analyses 
No interim analyses are planned. 
9.10 Quality control 
All staff collecting data for the study (site staff and/or external observers) will be provided 
with data collection guidelines and will receive training in the requirements of the study 
protocol and correct data collection. This will ensure consistent completion of the eCRF for 
demographic information, paper CRF for time and motion data collection, and administration 
of paper questionnaires to patients and caregivers.    
Data collection for the prospective time and motion study will be performed by trained 
external observers from the study management company or by members of the patients’ care 
team at each site, who will also receive training in the time and motion study procedures. The 
observers will record start and stop times for each task on paper CRFs. It is recommended 
that 2 timing devices are used in case of failure of one of the devices.  For the purposes of 
quality control, each data collector will transcribe the first 3 completed CRFs into the eCRF 
within 1 business day of the data collection and the entered data will be reviewed by project 
management or data management staff from the study management company. If errors or 
inconsistencies in the data are noted, additional training will be provided to the observers.  
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This pilot exercise will also be used to confirm that the database and CRF have been designed 
appropriately and that the data collection methodology is feasible.   
Data collection progress will be monitored by local Clinical Research Associates (CRAs) on an 
ongoing basis and support will be available throughout the entire study period to observers 
and site study staff as required. 
Patient demographic data and data submitted for the time and motion component of the 
study will be checked for completeness and accuracy by the Open Health data management 
team using agreed manual and programmed validation checks, which will be specified in the 
study DMP. Missing values may occur during collection of observational data (e.g. due to 
stopwatch failure). The frequency of these missing values will be tabulated as part of the data 
analysis but no queries will be raised. Other queries related to out-of-range values, 
inconsistent responses and any other data issues will be raised with each site by the data 
management team at the study management company, and resolutions documented.  Study 
centres will be required to co-operate with the data management team in the resolution of 
these queries. 
No queries will be raised on patient- or caregiver-reported data.  
9.11 Limitations of the research methods 
• 
Patient and caregiver consent is a requirement of this study; this may introduce 
selection bias and result in a study sample that may not be representative of the wider 
patient and caregiver population of interest. 
• 
Centres will be selected on the basis of interest in taking part in the study and 
experience in treating patients with FD with ERT. It is acknowledged that these centres 
may not be representative of current wider clinical practice in the countries of study.  
• 
For patient- and caregiver-reported outcomes, the data will rely on the completeness 
of the answers provided by participants, which will not be queried or otherwise 
followed up to clarify inconsistencies or omissions and may be subject to reporting 
bias. 
• 
A limitation of asking patients to complete questionnaires during their ERT infusion is 
that they may feel more anxious and/or tired when they are attending the hospital to 
receive treatment than at other times; consequently, the descriptions of patient-
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reported HRQoL and general wellbeing obtained in the study may be an overestimate 
of the overall impact of FD. 
• 
This is a descriptive study and no analyses to control for confounding will be carried 
out. For ethical reasons, time and motion data will not be stratified by individual staff 
member, although the performance of staff may be a factor in any observed 
variability. Experience levels of staff performing tasks observed in the study may vary 
between centres and may not reflect the experience level of staff performing the same 
tasks outside the study centres. There are also likely to be differences between the 
participating countries in local clinical protocols, healthcare settings and care 
processes, which may introduce variability in the data collected.  
• 
It is acknowledged that the time and motion evaluation may not capture the full 
burden of ERT administration since first infusions (which are expected to take longer 
than subsequent infusions) are excluded from the study; this is because the longer 
first infusion represents only a one-off burden at the start of long-term (potentially 
lifelong) treatment.     
• 
It is also acknowledged that QoL data could be impacted by ERT episodes that are 
close in timing to each other. 
10. 
Other aspects 
10.1 Review of study results 
Analysis of the primary endpoint, the total time spent by HCPs in the preparation and 
administration of a single dose of ERT in patients with FD, will be independently reviewed by 
a member of the Data Analysis team at Open Health who was not involved in the analysis of 
the final study data. No additional analysis checks will be carried out. 
It is anticipated that study results will be presented to investigators to enable a preliminary 
discussion of the results of the study, at a meeting to be planned after completion of the data 
analysis and before the study report is prepared. 
10.2 Study Amendments and Study Termination 
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Amendments to the study must be made only by prior agreement between the Amicus 
Therapeutics and Open Health. The Independent Ethics Committee (IEC)/Institutional Review 
Board (IRB) must be informed of all amendments and give approval for substantial 
amendments. The local Principal Investigator is responsible for obtaining approval from the 
IEC/IRB, and the local Clinical Research Organisation (CRO) supporting them will ensure a copy 
is forwarded to Amicus Therapeutics. 
Open Health, Amicus Therapeutics and Principal Investigators reserve the right to terminate 
participation in the study according to the study contract. Open Health will notify the IEC/IRB 
in writing of the study’s completion or early termination and send a copy of the notification 
to Amicus Therapeutics. 
11. 
Protection of human subjects 
This study will comply with all applicable laws, regulations, and guidance regarding patient 
protection including patient privacy, and consistent with the ethical principles of the 
Declaration of Helsinki24, the requirements of the General Data Protection Regulation 
(GDPR)25 and any other relevant local regulations. This study has been designed to minimise 
the data collected to that which is required for the planned analyses. The data collected will 
not include any direct identifiers. Data will be transferred to, and held securely by, Open 
Health at their offices within the UK during the conduct of this study, supported as needed by 
their local partners (refer to section 0).  
11.1 Ethical and regulatory approvals 
IEC/IRB approvals, competent authority and local management approvals for the conduct of 
this study and the sharing of anonymised-coded patient and caregiver data will be sought 
according to applicable local regulations.  
11.2 Ethical considerations 
This is an observational study involving a prospective time and motion study, completion of 
questionnaires by patients with FD and their caregivers and collection of demographic data 
from medical records; there will be no changes to patient management and no additional 
visits are required for the study. Only anonymised-coded data will be collected. 
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A participant information sheet will be provided to patients and caregivers identified as being 
eligible for study participation by the patient’s whole care team, explaining the above 
components of this research study. Only patients providing written informed consent (for one 
or both components) will be included in the study and no data collection will take place until 
written informed consent for the relevant component of the study has been provided. 
Caregivers will only be included if the patient with FD for whom they provide care or support 
has also consented to join the study. HCPs at the participating centres will give consent to be 
observed in their provision of care for the time and motion study. 
Patient- and carer-reported outcome data will be collected prospectively for those providing 
informed consent. Participation requires patients to complete a ~25-30 minute series of 
questionnaires related to the impact of FD on HRQoL, wellbeing, levels of fatigue and work 
productivity, which some may find upsetting. As most patients will complete the validated 
questionnaires during an ERT infusion, their HCPs will be able to provide support in the event 
that they do experience any distress. There will be no direct benefits of participation in the 
study but patients will be provided with a name and contact details for study-related queries.  
Patients and caregivers will be able to withdraw from the study at any time without any 
impact on the patient’s clinical care.   
11.3 Participant privacy 
The Data Controller for this study is Amicus Therapeutics. Data will be collected in 
anonymised-coded format and no personally identifiable information on any participant will 
be collected or removed from the hospitals or treatment centres participating in the study in 
order to preserve patient confidentiality. Participants will be assigned a study-specific unique 
identification number which will be referenced in a study log. This identification log will not 
leave the participating centre location and will be the responsibility of the principal 
investigator at that study centre. Anonymised-coded participant data will be processed for 
the purposes of the research study described in this protocol and will be shared with Amicus 
Therapeutics, Open Health, Klinikos, Zeincro and IQVIA within the European Economic Area 
(EEA) and,  intellim Holdings Corporation and Clinical Trial & Consulting based outside the EEA 
for the purposes of this research study. Companies located outside the EEA will maintain 
anonymised-coded data in accordance with the recognised EU Model Clause Agreement to 
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safeguard participant anonymity. Participant data will be retained for the archive period 
specified in section 11.4. Participants will be advised of their rights in respect of their data, 
including the right to raise any concerns or complaints related to this research study with the 
applicable local data protection regulator. 
11.4 Study Documentation and Archive 
Consistent with ENCePP/ISPE/GDPR guidance, the study documents and anonymised-coded 
data will be archived securely by Open Health on behalf of Amicus Therapeutics for a period 
of three years in the UK after the end of the study (defined as the date of the final signed 
Study Report). After this time, the electronic patient-level study data will be removed of 
unique study codes (i.e. completely anonymised) and transferred securely to Amicus 
Therapeutics for extended archiving in line with their standard archive period for non-clinical 
trials.  All other study documents will, with Amicus Therapeutics approval, be securely 
destroyed. The duration of archiving of study data will ensure that any queries arising from 
peer review of any ensuing publications can be addressed by reference to the source data if 
required. 
12. 
Management and reporting of adverse events / adverse reactions 
No patients will have received treatment with any Amicus Therapeutics medicinal products 
as part of this study, therefore it is not anticipated that Adverse Events (AEs), as defined 
below, will be required to be reported for study patients.   
However, any AEs reported by an HCP in relation to patients that have received an Amicus 
Therapeutics product in the course of normal clinical practice will be reported in line with the 
guidance below.  These events will be summarised in the safety reporting section of the final 
study report. 
Sites will be advised that any untoward medical occurrence in a patient in this study following 
administration of a non-Amicus Therapeutics medicinal product should be reported as an AE 
to the authority marketing the product by the patient’s HCP as per their local regulatory 
requirements.  
12.1 Definitions 
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Adverse Event:  Any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. 
Adverse Drug Reaction (ADR):  
As per the definition found in the WHO Technical Report 498 [1972], an adverse drug 
reaction is a response to a drug which is noxious and unintended and which occurs at doses 
normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of 
physiological function 
Product Complaints (PCs): 
Product Quality Complaint (PQC) – Any communication that alleges deficiencies related to 
the drug product as a result of manufacturing, packaging, or distribution and calls into 
question the identity, strength, quality, potency, purity, tampering and/or counterfeiting of 
that marketed drug product . Product Quality Complaints (PQCs) can involve reports of 
product defects, such as product appearance, packaging issues, taste/odour etc. PQCs can 
also contain adverse events e.g., lack of efficacy (failing to produce the expected 
pharmacological action for the approved indication). 
Non-Product Quality Complaint: 
A complaint that does not directly relate to product quality, purity, strength, potency, safety 
or effectiveness, such as a service complaint. 
Product Safety Events:  
Post marketing Safety Events collectively refer to: 
• All reports of AEs (non-serious and serious) 
• AEs associated with product complaints, or counterfeit products 
• Exposure during pregnancy and lactation (including paternal)  
• Reports of overdose, misuse, abuse, drug interaction  
• Medication error  
• Off-label use with or without an AE 
• Lack of efficacy  
• Occupational exposure 
• Suspected transmission of an infectious agent 
Clinical trial safety events refer to:   
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Events specified to be collected and reported to Amicus pharmacovigilance  (or designee) 
within the study protocol. This may include, but is not limited to serious adverse events, 
pregnancies, and overdose reports. 
Serious Adverse Event:   
A serious adverse event (experience) or reaction is any untoward occurrence that at any 
dose results in any of the following: 
• Life-threatening AE: (an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Death 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Medically significant: (events that may not be life-threatening, result in death, or 
require hospitalization but may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition above). 
Special Situations (SS):   
Circumstances where the report does not include an AE per se, but nevertheless needs to be 
reported to Amicus Therapeutics.  These circumstances include as per GVP module VI (use in 
a paediatric or elderly population, overdose, off-label use, abuse, misuse, medication error, 
lack of therapeutic effect /lack of effect (LOE), occupational exposure, falsified medicinal 
product, suspected transmission of an infectious agent via a product, drug interactions 
(including drug/food, drug/device, and drug/alcohol interactions, drug/food interactions), 
unexpected therapeutic effect, or worsening of an existing condition 
Unexpected Therapeutic Effect: a beneficial therapeutic effect of a Product aside from the 
use for which it had been given 
12.2 Reporting Procedures for Adverse Events 
12.2.1 Reporting Time-Frames 
OPEN VIE shall report all potential AEs, SSs, and all PCs to Amicus within 24 hours of receipt 
of the event and no later than 1 business day. Reporting responsibilities are the same for all 
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AEs, irrespective of the seriousness of the event or whether or not it was caused by the 
product. All SSs, and PCs should be reported, whether or not there is an associated AE.  
12.2.2 Reporting methodology 
AEs, SSs, and PCs should be reported via email to PhV.Migalastat SO@quintiles.com . 
12.3 Reconciliation 
At the end of the study (defined as after all study data is entered into the eCRF), IQVIA will 
email a report of cases received at IQVIA during the study to OPEN VIE. OPEN VIE is required 
to review the listing of cases and respond to IQVIA within 1 business day, confirming either 
that the list is correct or highlighting any discrepancies between the listing received from 
IQVIA and OPEN VIE records. Should OPEN VIE note that case reports are missing from the list 
provided by IQVIA, OPEN VIE will forward the missing report(s) within 1 business day via email 
to IQVIA at PhV.Migalastat SO@quintiles.com. IQVIA will follow up any discrepancies to 
resolution. 
13. 
Plans for disseminating and communicating study results 
Study results will be submitted for presentation at appropriate national and/or international 
conferences and may also be submitted for publication to appropriate peer reviewed 
journals; the primary endpoint will be reported in the first publication arising from this study. 
The study will be reported according to the requirements of STROBE (Strengthening the 
reporting of observational studies in epidemiology) as specified in the appropriate checklist 
for the study design27. 
Authorship of any publications arising from the study will follow the guidelines proposed by 
the International Committee of Medical Journal Editors (2015)30. All authors will meet the 
criteria for authorship, and all people who meet the criteria will be authors and all authors 
will agree to be accountable for the study. Potential conflicts of interest will be disclosed.  All 
authors will have:  
(1) made substantial contributions to conception or design or acquisition of data, or analysis 
and interpretation of data; AND 
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(2) participated in drafting the publication or revising it critically for important intellectual 
content; AND  
(3) approved the final version to be published. 
Each author will have participated sufficiently in the work to take public responsibility for 
appropriate portions of the content. Acquisition of funding, collection of data, or general 
supervision of the research group will not justify authorship.  
14. 
Study support 
The study is sponsored by Amicus Therapeutics. Amicus Therapeutics has commissioned Open 
Health to develop materials for and coordinate the conduct of the study, including protocol 
development, ethical and local approval, data collection, analysis and presentation of the 
results. 
Open Health is an independent consultancy specialising in the evaluation of healthcare 
services and interventions through observational research, with a focus on the design and 
implementation of 'Real World Data' projects in order to understand current healthcare 
practices.   
Open Health have commissioned local partner companies (Klinikos in Taiwan, Zeincro in 
Turkey, intellim Holdings Corporation in Japan and Clinical Trial & Consulting in Brazil) to 
perform local operations in these countries such as; site feasibility & identification, support 
of the sites to gain ethical and local hospital approval, data query management, site closure 
and local project management. 
Amicus Therapeutics commission IQVIA as their pharmacovigilance vendor for collating and 
reporting all pharmacovigilance events related to Migalastat.
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15. 
References 
1.  
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and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001 Nov 
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Germain DP. Fabry disease. Orphanet J Rare Dis. 2010 Nov 22;5:30.  
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Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death 
in males and females with Fabry disease: findings from the Fabry Registry. Genet Med 
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4.  
Arends M, Biegstraaten M, Wanner C, Sirrs S, Mehta A, Elliott PM, et al. Agalsidase alfa 
versus agalsidase beta for the treatment of Fabry disease: an international cohort 
study. J Med Genet. 2018 Feb 7;  
5.  
Arends M, Hollak CEM, Biegstraaten M. Quality of life in patients with Fabry disease: a 
systematic review of the literature. Orphanet J Rare Dis. 2015 Jun 16;10:77.  
6.  
Arends M, Körver S, Hughes DA, Mehta A, Hollak CEM, Biegstraaten M. Phenotype, 
disease severity and pain are major determinants of quality of life in Fabry disease: 
results from a large multicenter cohort study. J Inherit Metab Dis. 2018 Jan;41(1):141–
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Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. 
Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern 
Med. 2007 Jan 16;146(2):77–86.  
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Alegra T, Vairo F, de Souza MV, Krug BC, Schwartz IVD. Enzyme replacement therapy 
for Fabry disease: A systematic review and meta-analysis. Genet Mol Biol. 2012 
Dec;35(4 Suppl):947–54.  
9.  
Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf MGW, Hollak CEM. Long 
term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart 
and brain. Orphanet J Rare Dis. 2013 Mar 25;8:47.  
10.  Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, et al. Ten-year 
outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry 
disease. J Med Genet. 2015 May;52(5):353–8.  
11.  Hughes DA, Mlilligan A, Mehta A. Home therapy for lysosomal storage disorders. Br J 
Nurs Mark Allen Publ. 2007 Jan 13;16(22):1384, 1386–9.  
12.  Cousins A, Lee P, Rorman D, Raas-Rothschild A, Banikazemi M, Waldek S, et al. Home-
based infusion therapy for patients with Fabry disease. Br J Nurs Mark Allen Publ. 2008 
Jun 22;17(10):653–7.  
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13.  Milligan A, Hughes D, Goodwin S, Richfield L, Mehta A. Intravenous enzyme 
replacement therapy: better in home or hospital? Br J Nurs Mark Allen Publ. 2006 Apr 
23;15(6):330–3.  
14.  Concolino D, Amico L, Cappellini MD, Cassinerio E, Conti M, Donati MA, et al. Home 
infusion program with enzyme replacement therapy for Fabry disease: The experience 
of a large Italian collaborative group. Mol Genet Metab Rep. 2017 Sep;12:85–91.  
15.  Guest JF, Concolino D, Di Vito R, Feliciani C, Parini R, Zampetti A. Modelling the 
resource implications of managing adults with Fabry disease in Italy. Eur J Clin Invest. 
2011 Jul;41(7):710–8.  
16.  Wyatt K, Henley W, Anderson L, Anderson R, Nikolaou V, Stein K, et al. The 
effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: a 
longitudinal cohort study of people with lysosomal storage disorders. Health Technol 
Assess Winch Engl. 2012;16(39):1–543.  
17.  The MPS Society and Shire Pharmaceuticals. Living with Fabry Disease: A Market 
Research Study [Internet]. 2014. Available from: http://www.mpssociety.org.uk/wp-
content/uploads/2016/07/fabry_patient_report_v1_17th_march_2014.pdf 
18.  von der Lippe C, Frich JC, Harris A, Solbrække KN. Experiences of Being Heterozygous 
for Fabry Disease: a Qualitative Study. J Genet Couns. 2016;25(5):1085–92.  
19.  Ware J, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of 
scales and preliminary tests of reliability and validity. Med Care. 1996 Mar;34(3):220–
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20.  A Prospective, Observational Registry of Patients with Fabry Disease. UBC;  
21.  Psychiatric Research Unit, WHO Collaborating Centre in Mental Health. WHO (Five) 
Well-Being Index (1998 version) [Internet]. 1998 [cited 2018 Oct 31]. Available from: 
https://www.psykiatri-regionh.dk/who-5/Documents/WHO5_English.pdf 
22.  Recht M, Neufeld EJ, Sharma VR, Solem CT, Pickard AS, Gut RZ, et al. Impact of acute 
bleeding on daily activities of patients with congenital hemophilia with inhibitors and 
their caregivers and families: observations from the Dosing Observational Study in 
Hemophilia (DOSE). Value Health J Int Soc Pharmacoeconomics Outcomes Res. 2014 
Sep;17(6):744–8.  
23.  Robinson BC. Validation of a Caregiver Strain Index. J Gerontol. 1983 May;38(3):344–8.  
24.  Population, total | Data [Internet]. [cited 2019 Mar 28]. Available from: 
https://data.worldbank.org/indicator/SP.POP.TOTL?locations=TR-BR-JP 
25.  World Medical Association. WMA Declaration of Helsinki – Ethical Principles for 
Medical Research Involving Human Subjects [Internet]. 2013 Oct [cited 2018 Apr 6]. 
Available from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-
ethical-principles-for-medical-research-involving-human-subjects/ 
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26.  European Union. General Data Protection Regulation [Internet]. 2018 May [cited 2018 
Apr 6]. Available from: http://eugdpr.org/the-regulation.html 
27.  STROBE Initiative. STROBE Statement: Available checklists [Internet]. 2009 [cited 2017 
Sep 6]. Available from: https://www.strobe-statement.org/index.php?id=available-
checklists 
28.  International Committee of Medical Journal Editors (ICMJE). ICMJE uniform 
requirements for manuscripts [Internet]. 2017 [cited 2017 Sep 6]. Available from: 
http://www.icmje.org/about-icmje/faqs/icmje-recommendations/ 
 
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16. 
Annex 1 Adverse event, special situation and product complaints 
intake form 
 
 
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17. 
Annex 2 Study questionnaires 
 
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