Patient Experience and Preference (PEP) Study in nAMD and DME - Study Protocol - MR41928
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Patient Experience and Preference (PEP) Study in nAMD and DME Study Protocol – MR41928 Version 1.0 – 20 October 2020
Signature Page
Title: Patient Experience and Preference (PEP) Study in nAMD and DME
Protocol number: MR41928
Version: Version 1.0 – 20 October 2020
Signature of responsible person at sponsor
The signatory agrees to the content of the final protocol as presented.
Name: Role:
Date: Signature:
Signature of responsible person at ICON
The signatory agrees to the content of the final protocol as presented.
Name: Role:
Date: Signature:
Signature of Investigator
The signatory agrees to the content of the final protocol as presented.
Name: Role:
Date: Signature:
MR41928 Protocol, Version 1.0, 20 October 2020
2Administrative Structure
Sponsor Contact
Global Studies Leader (GSL), I2ON, PDG
F. Hoffmann-La Roche Ltd
Operator Contact
Principal, ICON plc
MR41928 Protocol, Version 1.0, 20 October 2020
3Protocol Synopsis
Parameter Description
Objective
Primary Objectives
● Identify and describe reasons for not being able or willing to follow management plan
(i.e. non-adherence) to anti-VEGF IVT injections among patients living with
neovascular age-related macular degeneration (nAMD) or diabetic macular edema
(DME);
● Understand the factors that impact anti-VEGF IVT treatment satisfaction from the
perspectives of the patients and caregivers;
● Assess associations between aspects of the patient experience (e.g., ability or
willingness to follow management plan (i.e., adherence), barriers, burden,
satisfaction) and treatment patterns and outcomes (both clinically measured and
patient-reported), including visual acuity;
● Investigate stated patient preference for aspects of treatment via a discrete choice
experiment.
Secondary Objectives
● For patients, understand aspects of treatment burden with current anti-VEGF IVT
injections, including, but not limited to, clinic access/logistics, impacts on work/daily
living, productivity loss, insurance coverage, financial impacts, frequency of treatment
administration, burden related to monitoring and injection visits, burden of managing
adverse events and post-treatment recovery, physical impacts, and psychological
concerns regarding IVT injections;
● For caregivers, understand aspects of treatment burden with current anti-VEGF IVT
injections, including, but not limited to, clinic access/logistics, impacts on work/daily
living, productivity loss, financial impacts, frequency of treatment administration,
burden related to monitoring and injection visits, burden of managing adverse events
and post-treatment recovery of the patient, physical impacts, and psychological
impacts of caregiving on caregivers;
● Assess health-related quality of life, vision-related functioning and treatment
satisfaction using patient-reported outcome (PRO) instruments, and caregiver
perceptions using an appropriate caregiver self-report instrument.
Background
Prior to commencing the present study, qualitative research was undertaken in order to
inform the development of cross-sectional surveys for patients and their caregivers (4
surveys). This research consisted of:
● A targeted literature review;
● Patient living with nAMD or DME and caregiver qualitative concept elicitation
telephone interviews;
● Physician qualitative concept elicitation telephone interviews;
The scope of the qualitative interviews included the United States (US), Canada, France,
Germany, Italy and Spain. The literature review and the collected qualitative data informed
the development of four draft surveys – one for patients and one for caregivers for each
condition (nAMD and DME). The surveys on treatment experience, adherence, satisfaction,
and preference included de novo questions, existing validated PRO and caregiver self-report
instruments, and a Discrete Choice Experiment (DCE) component to assess treatment
preferences. The selection of validated instruments and development of de novo questions
MR41928 Protocol, Version 1.0, 20 October 2020
4were also informed by the results of the qualitative interviews and literature review. Cognitive
interviews were held with patients identified through patient advocacy organizations to
ensure both the content and format of the draft surveys were appropriate and relevant for
patients and caregivers. The surveys were then finalized based on all of the feedback
received and translated into the target languages for use in this study.
Study Design
This is a multi-national, cross-sectional, non-interventional study (NIS) employing a
quantitative survey and discrete choice experiment (DCE) administered among patients
living with nAMD and DME and their caregivers. Medical chart extraction will be conducted
to obtain clinical information (e.g., anti-VEGF treatments and visual acuity) for patients
participating in the survey. Aspects of the patient experience assessed by the survey will be
associated with treatment patterns and clinical outcomes extracted from medical records.
The target countries are:
● United States (US)
● Canada
● France
● Germany
● Italy
● Spain
● United Kingdom (UK)
This non-interventional, cross-sectional study will comprise the fielding of the surveys in all
countries and the analysis of results. Participants will be recruited via clinical sites. To
accommodate vision issues, the surveys will allow for administration in multiple formats (i.e.,
paper, online, or telephone) and will use appropriate font sizes (where applicable). All survey
responses, regardless of whether they were originally collected via paper or telephone, will
be entered into an electronic data capture system. In parallel for each patient completing the
survey, medical records will be reviewed to extract information on patient sociodemographic
characteristics, medical history, treatments received including anti-VEGF treatments,
comorbidities, and visual acuity. All data will be entered by the sites into electronic case
report forms (eCRFs).
During the course of the study, payers from the targeted countries were consulted to ensure
the planned data collection in this study are appropriate and can be used to address the
study objectives. Patient advocacy organization representatives were also consulted to
ensure the relevance and appropriateness of the procedures and data collected.
Study
Population The target population for this study is adult patients living with nAMD or DME and their
caregivers as defined below. Participants will be recruited via clinical sites in the US, Canada,
France, Germany, Italy, Spain, and the UK.
Sample Size
A target of approximately 1800 adult participants (n=100 patients, per country, per condition
in UK/Italy/France/Spain/Germany, and 200 per condition in the US and Canada) will
complete the survey. Between 360 and 720 caregivers equally balanced between the two
conditions will complete the survey, representing a target of 20-40% of the target patient
number.
Survey Fielding
Country Number of Patients Number of Caregivers
(nAMD/DME) (nAMD/DME)
MR41928 Protocol, Version 1.0, 20 October 2020
5UK 200 40 to 80
Italy 200 40 to 80
Germany 200 40 to 80
US 400 80 to 160
Canada 400 80 to 160
France 200 40 to 80
Spain 200 40 to 80
TOTAL 1800 360 to 720
Eligibility
Criteria Inclusion Criteria
Patients
1. Aged 18 years or older with a physician-confirmed diagnosis of either nAMD or DME
2. Willing and able to provide written informed consent (where applicable by local
regulations)
3. Have had anti-VEGF IVT injection treatment initiated at least 6 months before March
2020, to ensure patients have treatment experience prior to the COVID-19 outbreak
a. Most recent anti-VEGF IVT injection should have occurred within 6 months
of the screening date
4. Have a minimum of 18-month medical records data available to the site for extraction
5. Willing and able to complete an approximately 30-minute survey, if excluding the
DCE part, or up to 1 hour, if including the DCE part, either online, paper, or by
telephone interview
6. Able to read, write or speak fluently in the local language in which the survey is
conducted, as relevant per country
Caregivers
1. Aged 18 years or older
2. Be the primary caregiver* of an adult patient (aged 18 years or older) with a
physician-confirmed diagnosis of either DME or nAMD
a. Preferences for caregiver/patient dyads (pairs)
3. Willing and able to provide written informed consent (where applicable by local
regulations)
4. Willing and able to complete an approximately 30-minute survey, either online,
paper, or by phone
5. Able to read, write or speak fluently in the local language in which the survey is
conducted, as relevant per country
* For the purpose of this study, “primary” caregiver is defined as
a.) the main person responsible for the patient’s daily care, who has had contact with the
patient on most days, for most of the time that the patient was at home during the past 12
months
OR
b.) for some patients, in particular younger patients, who might not have a daily caregiver,
the primary caregiver can be the main person who accompanies the patient on treatment
visits or provides support for specific activities like shopping or traveling to places.
Note: Primary caregivers are intended to be family or friends, not paid caregivers.
Exclusion Criteria
MR41928 Protocol, Version 1.0, 20 October 2020
6Patients and caregivers will be excluded from participation if they meet any of the following
criteria:
1. As per the investigator’s own judgement, any serious psychiatric disorder or other
condition (e.g., Alzheimer’s disease, dementia, schizophrenia, current or history of
substance abuse, or appearance of being impaired/under the influence) that impairs
memory or cognitive function to the extent that it could interfere with the participant
providing informed consent or completing questionnaires
2. Currently enrolled in any clinical trial for any conditions
3. Patients who are receiving or have ever received anti-VEGF therapy in a clinical trial
for retinal diseases
4. For patients with nAMD
a. Any current or history of DME, retinal vein occlusion, or myopic choroidal
neovascularization
b. Any current or history of diabetic retinopathy treated with anti-VEGF IVT
5. For patients with DME, any current or history of nAMD, retinal vein occlusion, or
myopic choroidal neovascularization
Study
Procedures Survey content and completion
A total of four surveys were developed: one for patients and one for caregivers, for each
condition (nAMD and DME). The surveys will ask participants questions about their disease
experience or their experience as caregivers of patients living with nAMD or DME, as well
as treatment-related topics including satisfaction, ability and willingness to follow
management plan, and preference. For that purpose, the surveys include de novo questions
as well as existing PRO and caregiver self-report instruments, and the DCE component. The
final selection of validated instruments was supported by the findings from the qualitative
research. The de novo questions and the DCE component were developed based on the
qualitative research to ensure understanding and relevance of the items.
Due to concerns regarding low-vision, participants will have the option to take the survey
online, on paper with enlarged font and/or specific background/font color combinations to
optimize visibility, or via telephone. Participants willing to take the survey via telephone or by
paper will be asked to share their preference with their contact details for the ICON Direct-
to-Patient Contact (DPC) team to administer the survey by phone, or to ship the paper survey
to their home with a prepaid return envelope, and to remind them to complete it when
applicable.
Separately, all data extracted from patient medical records will be entered by the sites into
eCRFs. Data extraction will be performed by site staff only. Roche and ICON will not have
access to the participant’s medical records for source data verification. A Site Operations
Representative will perform source data verification (SDV) as defined in the Clinical
Monitoring Plan (CMP) to confirm that critical protocol data (i.e., source data) entered in the
CRF by authorized site personnel are accurate, complete, and verifiable from source
documents.
Each participant will be allocated a participant number to allow the linkage of survey data to
eCRF data. As a site extracts data from patient records and enters them into the electronic
data capture (EDC) system, a patient ID will be created and then the surveys will be
conducted using this patient ID.
eCRF content and completion
Sites will be asked to extract and enter into the EDC a series of socio-demographic and
clinical information. Patients’ medical records will be screened to extract information on their
adherence to their visits and treatments in relation to the conditions of interest (i.e. nAMD
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7and DME) over the past 12 to 18 months, as well as clinical information including visual
acuity and comorbidities
Remuneration
Participants will be remunerated if allowed and in accordance with local regulations, as
specified in the informed consent document.
Ethical and
Regulatory Applicable regulatory and ethics submissions will be performed in each country prior to
Requirements recruitment initiation.
Data collected for study purposes will strictly adhere to confidentiality regulations and
legislation, including EU General Data Protection Regulation (GDPR), US Health Insurance
Portability and Accountability Act (HIPAA), and the Canadian Personal Information
Protection and Electronic Documents Act (PIPEDA).
If the research study is to be published or publicly reported, results will not contain any
identifying information.
MR41928 Protocol, Version 1.0, 20 October 2020
8Contents
1. Introduction 12
2. Objectives 14
2.1.1. Primary Objectives 14
2.1.2. Secondary Objectives 14
3. Methods 15
3.1. Study Design 15
3.2. Study Population 16
3.2.1. Eligibility Criteria 16
3.2.1.1. Inclusion Criteria 16
3.2.1.2. Exclusion Criteria 17
3.2.2. Sample Size 17
3.2.2.1. Sample Size Implications 18
3.3. Participant Recruitment 18
3.4. Study Materials 19
3.5. Study Procedures 20
3.6. Variables and Data sources 21
3.6.1. Survey - Participant Characteristics 22
3.6.2. Survey - De Novo Questions 22
3.6.3. Survey - PRO and Caregiver Self-Report Instruments 23
3.6.3.1. NEI-VFQ-25 23
3.6.3.2. RetTSQ 24
3.6.3.3. MacTSQ 24
3.6.3.4. Caregiver Reaction Assessment 24
3.6.4. Survey – DCE Component 25
3.6.5. eCRF 25
3.7. Analysis 26
3.8. Limitations of the Research Method 27
4. Data Management 28
4.1. Data Management 28
4.2. Source Data Verification 28
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94.3. Study Documentation and Monitoring 29
4.3.1. Study Documentation 29
4.3.2. Site Audits and Inspections 29
4.3.3. Use of Site Computerized Systems 29
4.3.4. Retention of Records 29
5. Protection of Human Subjects 31
5.1. Informed Consent 31
5.2. Potential Risks and Benefits 31
5.3. Confidentiality 31
5.4. Withdrawal from Study 32
5.5. Compliance with Laws and Regulations 32
5.6. Institutional Review Board or Ethics Committee 32
6. Publication of Data and Protection of Trade Secrets 33
7. Management of Adverse Events 34
8. References 35
9. Appendices 37
MR41928 Protocol, Version 1.0, 20 October 2020
10Abbreviations
Abbreviation Full description
AE Adverse event
Ang2 Angiopoietin-2
CE Concept elicitation
CI Cognitive interviews
CMP Clinical monitoring plan
CNV Choroidal neovascularization
DCE Discrete choice experiment
DME Diabetic macular edema
DPC ICON’s Direct-to-Patient Contact team
DR Diabetic retinopathy
eCRF Electronic case report form
EDC Electronic data capture
EQ-5D Euroqol EQ-5D questionnaire
ICD Informed consent document
IRB Institutional Review Board
ISPE International Society of Pharmacoepidemiology
ISPOR International Society for Pharmacoeconomics and Outcomes Research
IVT Intravitreal injections
MacTSQ Macular Disease Treatment Satisfaction Questionnaire
nAMD Neovascular age-related macular degeneration
NEI-VFQ National Eye Institute Visual Function Questionnaire
NIS Non-interventional study
PAO Patient advocacy organization
PCO ICON’s Patient Centered Outcomes team
PRO Patient-reported outcome
RetTSQ Retinopathy Treatment Satisfaction Questionnaire
SAP Statistical analysis plan
SDV Source data verification
UK United Kingdom
US United States of America
VA Visual acuity
VEGF Vascular endothelial growth factor
MR41928 Protocol, Version 1.0, 20 October 2020
111. Introduction
Age-related macular degeneration (AMD) is a neurodegenerative disease of the central retina that
causes irreversible destruction of the macula, which leads to loss of the sharp, fine-detail, “straight
ahead” vision that is required for activities such as driving, reading, seeing in color and recognizing
faces (1). Choroidal neovascularization (CNV) secondary to AMD (or neovascular AMD) is a phenotype
of AMD, which is characterized by formation of new vessels in the choroid (capillaries under the retina)
which protrude through Bruch’s membrane and into the retina (2). A complex immunological interplay
causes this neovascularization wherein secretion of vascular endothelial growth factor (VEGF) as well
as the cytokine angiopoietin-2 (Ang2) are important driving forces (3, 4). Neovascular AMD (nAMD)
accounts for most cases of AMD‐related severe vision loss (4), and owing to age being a risk factor for
nAMD, the incidence of nAMD is projected to increase with the aging of the population (5, 6).
Diabetic macular edema (DME) is a common microvascular complication in patients with diabetes and
may have a sudden and debilitating impact on visual acuity (VA) that can eventually lead to blindness
(7, 8). DME is a complication of diabetic retinopathy (DR), which is characterized by the growth of
abnormal retinal blood vessels secondary to ischemia. At any point during the progression of DR,
patients can also develop DME, which involves retina thickening in the macular area. More specifically,
DME occurs after breakdown of the blood-retinal barrier because of leakage of dilated hyperpermeable
capillaries and microaneurysms (9). Type 2 diabetes has reached epidemic proportions, fueled by the
rapid increase in obesity and an aging population (7). DR is a major cause of vision loss in patients
with diabetes. The longer patients have diabetes, the higher the prevalence of DR (10). DME is a
frequent manifestation of DR (7) and is a leading cause of legal blindness in patients with Type 2
diabetes. Owing to the increasing prevalence of Type 2 diabetes, the incidence of DME is projected to
follow a similar trend (10).
Both nAMD and DME can affect VA and can eventually lead to blindness. People diagnosed with either
nAMD or DME may experience significant reduction in functional status and quality of life. Indeed,
studies have shown that individuals diagnosed with nAMD experience poor quality of life because of
the difficulties they experience in performing daily activities and the impact of their disease on their
emotional well-being (11, 12). Similarly, studies have shown that diabetic patients diagnosed with DME
report a decline in quality of life and daily functioning with increasing visual impairment (13). Quality of
life impacts are further compounded by the healthcare and economic burdens of both diseases on the
society (7-14).
Neovascular AMD and DME both require ongoing treatment with regular follow-up and monitoring to
control disease activity. Anti-vascular endothelial growth factor (anti-VEGF) therapies (e.g.,
ranibizumab, aflibercept) have been successful in improving and preserving vision and quality of life
for patients living with nAMD or DME (1, 15). However, evidence suggests that real-world outcomes
for patients living with nAMD or DME lag behind those documented in clinical trials (1, 15). Insufficient
management of nAMD and DME, mainly attributed to the burden of treatment on patients, carers, and
the healthcare system (i.e., frequent anti-VEGF intravitreal (IVT) injections), have been reported to
result in patients receiving fewer anti-VEGF IVT injections and less frequent monitoring and/or not
being able to follow the management plan (1, 15). Despite the potential benefits of anti-VEGF
treatments, innovations are needed in nAMD and DME management to improve treatment ability or
willingness to follow management plan (i.e. adherence) that will lead to improved outcomes.
Considering the challenges that patients experience with anti-VEGF IVT injections, identifying and
examining the drivers of non-adherence to anti-VEGF IVT injections and patients’ treatment
MR41928 Protocol, Version 1.0, 20 October 2020
12preferences are of interest in order to ensure that the new technologies are safe and effective,
acceptable to patients, and lead to better outcomes for patients.
Studies on treatment preferences suggest that patients prefer treatments that will improve VA, but will
not add additional complexity to their lives. For example, a few studies report that patients prefer
treatments that are effective (improve VA), and treatments with low burden for patients and their
caregivers, including longer treatment intervals, reduced appointment waiting times in the clinic and
travel time to and from the hospital (16-18).
Understanding the preferences of patients for different benefits that therapies provide can be
challenging, but methodologies exist that can help in this effort. A discrete choice experiment (DCE) is
an attribute-based survey method which can be used in this context. DCEs involve presenting
respondents with a sequence of hypothetical scenarios (choice sets) composed of two or more
competing alternatives that differ along several attributes (19). Over the past decade, DCEs have been
increasingly utilized to help understand preferences in the field of health and healthcare (20-23). DCEs
are based on the premise that any goods or service can be described by their characteristics (or
attributes) and, secondly, the extent to which an individual values a good or bad service can be
described in terms of the levels of these characteristics (21). The technique involves presenting
individuals with choices of hypothetical scenarios described in terms of attributes and associated
levels. Participants are asked to choose their preferred scenario.
This study will aim to further understand (in the context of current IVT standard of care) the current
treatment experiences, satisfaction, and barriers to adherence in nAMD and DME from patients’,
caregivers’, and physicians’ perspectives in a multinational setting and to suggest how any future
therapies, might improve the patient treatment experience through sustained efficacy (i.e., longer
interval between IVT injections) or ease of use.
Prior to commencing the present study, qualitative research was undertaken in order to inform the
development of cross-sectional surveys for patients and their caregivers (4 surveys). This research
consisted of:
● A targeted literature review;
● Qualitative concept elicitation telephone interviews with patients living with nAMD or DME and
caregivers;
● Qualitative concept elicitation telephone interviews with physicians treating patients living with
nAMD or DME.
The literature review and the collected qualitative data informed the development of four draft surveys
– one for patients and one for caregivers for each condition (nAMD and DME). The patient surveys on
treatment experience, adherence, satisfaction, and preference included de novo questions, existing
validated patient-reported outcome (PRO) instruments, and a Discrete Choice Experiment (DCE)
component to assess treatment preferences. The caregiver surveys on the caregiving experience and
impacts and perspective on care recipient’s treatment experience included de novo questions and a
caregiver self-report measure. The selection of measures and development of de novo questions were
informed by the results of the qualitative interviews and the literature review. Cognitive interviews were
held with patients identified through patient advocacy organizations (PAOs) to ensure both the content
and format of the draft surveys were appropriate and relevant for patients and caregivers. The surveys
were then finalized based on all of the feedback received for use in this study. The surveys were
translated into the targeted languages using dual forward translation and back translation
methodology.
MR41928 Protocol, Version 1.0, 20 October 2020
13This protocol describes the survey fielding and medical record extraction, including the deployment of
the survey and data collection.
2. Objectives
2.1.1. Primary Objectives
● Identify and describe reasons for not being able or willing to follow management plan (i.e. non-
adherence) to anti-VEGF IVT injections among patients living with nAMD or DME;
● Understand the factors that impact anti-VEGF IVT treatment satisfaction from the perspectives
of the patients and caregivers;
● Assess associations between aspects of the patient experience (e.g., ability or willingness to
follow management plan (i.e. adherence), barriers, burden, satisfaction) and treatment patterns
and outcomes (both clinically measured and patient-reported), including visual acuity;
● Investigate patient stated preference for aspects of treatment via a discrete choice experiment.
2.1.2. Secondary Objectives
● For patients, understand aspects of treatment burden with current anti-VEGF IVT injections,
including, but not limited to, clinic access/logistics, impacts on work/daily living, productivity
loss, insurance coverage, financial impacts, frequency of treatment administration, burden
related to monitoring and injection visits, burden of managing adverse events and post-
treatment recovery, physical impacts, and psychological concerns regarding IVT injections;
● For caregivers, understand aspects of treatment burden with current anti-VEGF IVT injections,
including, but not limited to, clinic access/logistics, impacts on work/daily living, productivity
loss, financial impacts, frequency of treatment administration, burden related to monitoring and
injection visits, burden of managing adverse events and post-treatment recovery of the patient,
physical impacts, and psychological impacts of caregiving on caregivers;
● Assess health-related quality of life, vision-related functioning and treatment satisfaction using
PRO instruments, and caregiver perceptions using an appropriate caregiver self-report
instrument.
MR41928 Protocol, Version 1.0, 20 October 2020
143. Methods
3.1. Study Design
This is a multi-national, cross-sectional, non-interventional study (NIS) employing a 2-part quantitative
survey made of de novo questions and PRO instruments for the first part and a DCE for the second
part. The survey will be administered among patients living with nAMD and DME. In parallel caregivers
of those patients will be invited to complete a survey made of de novo questions and a caregiver self-
report measure. Medical chart extraction will be conducted to obtain clinical information (e.g., patient
sociodemographic characteristics, geographical region, medical history, treatments received including
anti-VEGF treatments, comorbidities, and visual acuity) for patients participating in the survey. Aspects
of the patient and caregiver experience assessed by the survey will be associated with treatment
patterns and clinical outcomes extracted from medical records. The target countries are:
● United States (US)
● Canada
● France
● Germany
● Italy
● Spain
● United Kingdom (UK)
This cross-sectional NIS will comprise the fielding of the surveys in all countries and the analysis of
results. Participants will be recruited via clinical sites.
To accommodate potential challenges in survey administration due to visual impairment, the surveys
will be available in multiple formats (i.e., paper, online, or via telephone interview) and appropriate font
sizes (where applicable). The following formatting parameters will be implemented to ensure the
optimal comfort for the survey completion:
● No use of italics, however bold text will be used to put an emphasis on a word or part of a
sentence when needed
● Left alignment for the text will be used, no justified alignment
● A font size of at least 14 points but not more than 18 points will be used
● Arial or Verdana font will be used
● White spaces between items and between response options will be integrated
● For the paper version, black text on white background and simple white matte paper will be
used, while for the online version yellow text on black background will be used.
All survey responses, regardless of whether they were originally collected via paper, online or
telephone, will be entered into an EDC system.
In parallel to each patient completing the survey, medical records or administrative databases will be
reviewed by site investigator or staff to extract available information on patient adherence to their
monitoring and injection visits, treatments over the past 18 months, vision outcomes, and other
potentially relevant characteristics to be included in the analysis.
Non-adherence will be defined in this study as: Over the past 12 months, the patient
a. Had at least two scheduled monitoring or treatment visits where the patient did not attend or
cancelled AND did not return for a subsequent visit within four weeks
OR
MR41928 Protocol, Version 1.0, 20 October 2020
15b. Rescheduled at least two monitoring or treatment visits by more than four weeks after the
intended date.
The definition of non-adherence was informed based on discussion with payers, representatives of
PAOs, and qualitative interviews with physicians, and the literature and discussion with key opinion
leaders (24). The definition of non-adherence definition might be seen as less stringent than what has
been used in the literature, however it took into consideration the COVID-19 situation that affected all
countries. All data allowing the assessment of adherence will be entered by the sites into eCRFs.
During the preparation of this protocol, payers from the targeted countries were consulted as to whether
the planned data collection was in line with their expectations, and the study design appropriate,
thereby ensuring that important and relevant information is being collected. Additionally, PAO
representatives have been consulted to ensure the relevance and appropriateness of the procedures
and data collected.
The study start date will be the date of the first data collection, i.e., the date from which information on
the first study subject is recorded in the study database. The planned start date is 2 November 2020.
The end of the study will be the date from which the last information of the last subject is recorded in
the study database. The planned end of study date is 25 May 2021.
3.2. Study Population
The target population for this study is adult patients living with nAMD or DME and their caregivers.
Participants will be recruited from the US, Canada, France, Germany, Italy, Spain, and the UK.
3.2.1. Eligibility Criteria
The inclusion and exclusion criteria for participants are described below.
3.2.1.1. Inclusion Criteria
Participants will have to meet all of the following criteria:
Patients
1. Aged 18 years or older with a physician-confirmed diagnosis of either nAMD or DME
2. Willing and able to provide written informed consent (where applicable by local regulations)
3. Have had anti-VEGF IVT injection treatment initiated at least 6 months before March 2020, to
ensure patients have treatment experience prior to the COVID-19 outbreak
a. Most recent anti-VEGF IVT injection should have occurred within 6 months of the
screening date
4. Have a minimum of 18-month medical records data available for extraction
5. Willing and able to complete a survey either online, paper, or by telephone interview; the survey
will last approximately 30 minutes without the DCE part, or up to 1 hour, with the DCE included,
6. Able to read, write or speak fluently in the local language in which the survey is conducted, as
relevant per country
Caregivers
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161. Aged 18 years or older
2. Be the primary caregiver* of an adult patient (aged 18 years or older) with a physician-
confirmed diagnosis of either DME or nAMD
a. Preferences for caregiver/patient dyads (pairs)
3. Willing and able to provide written informed consent (where applicable by local regulations)
4. Willing and able to complete an approximately 30-minute survey, either online, paper, or by
phone
5. Able to read, write or speak fluently in the local language in which the survey is conducted, as
relevant per country
* For the purpose of this study, “primary” caregiver is defined as
a.) the main person responsible for the patient’s daily care, who has had contact with the patient on
most days, for most of the time that the patient was at home during the past 12 months.
OR
b.) For some patients, in particular younger patients, who might not have a daily caregiver, the primary
caregiver can be the main person who accompanies the patient on treatment visits or provides support
for specific activities like shopping, traveling to places.
Note: Primary caregivers are family or friends, not paid caregivers.
3.2.1.2. Exclusion Criteria
Patients and caregivers will be excluded from participation if they meet any of the following criteria:
1. As per the investigator’s own judgement, any serious psychiatric disorder or other condition
(e.g., Alzheimer’s disease, dementia, schizophrenia, current or history of substance abuse, or
appearance of being impaired/under the influence) that impairs memory or cognitive function
to the extent that it could interfere with the participant providing informed consent or completing
questionnaires,
2. Currently enrolled in any clinical trial for any conditions
3. Patients who are receiving or have ever received anti-VEGF therapy in a clinical trial for retinal
diseases
4. For patients with nAMD,
a. Any current or history of DME, retinal vein occlusion, or myopic choroidal
neovascularization
b. Any current or history of diabetic retinopathy treated with anti-VEGF IVT
5. For patients with DME, any current or history of nAMD, retinal vein occlusion, or myopic
choroidal neovascularization
3.2.2. Sample Size
Table 1 below presents the detailed number of participants in this survey study per country. A target
of approximately 1800 total adult participants (n=100 patients, per country, per condition in
UK/Italy/France/Spain/Germany, and 200 per condition in the US and Canada) will complete the
survey. Between 360 and 720 caregivers balanced between the two conditions will complete the
survey, representing a target of 20-40% of the target patient number. The preference is to recruit
caregiver/patient dyads (pairs) and not to recruit caregivers without a participating patient for whom
they provide care.
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17Table 1 Survey sample size per country
Country Number of Patients Number of Caregivers
(nAMD/DME) (nAMD/DME)
nAMD DME nAMD DME
UK 100 100 20 to 40 20 to 40
Italy 100 100 20 to 40 20 to 40
Germany 100 100 20 to 40 20 to 40
US 200 200 40 to 80 40 to 80
Canada 200 200 40 to 80 40 to 80
France 100 100 20 to 40 20 to 40
Spain 100 100 20 to 40 20 to 40
TOTAL 900 900 180 to 360 180 to 360
All patient participants will complete the cross-sectional questionnaire survey component (de novo
questions and PRO instruments). Patients will be asked also to complete the DCE survey; all European
participants will be asked to complete the DCE and 50% of the US and Canadian participants will be
asked to opt-in. For the US and Canada, the number of completes for the opt-in DCE component will
be monitored and the option to opt in will be removed when the threshold of 50% of the planned sample
of participants is passed.
3.2.2.1. Sample Size Implications
The appropriateness of the target sample sizes can be provisionally evaluated by calculating the
minimum effect sizes that could be detected in multiple linear regression models. Given a sample size
of 100 participants (per country per condition) and assuming a total of 10 predictors of which 3 are
tested, we would be able to detect a moderate effect size (f²) of 0.11 with an alpha of 0.05 and 80%
power (G*Power, version 3.1, 2017) (25).
Sample size calculation for DCEs in health care is particularly complex and unique to each study, as it
depends on a priori hypotheses of parameter estimates or effect sizes which are usually unknown
(especially in the absence of quantitative pilot testing) as well as characteristics of the experimental
design and the type of statistical model. As such, in the vast majority of preference studies, researchers
do not perform power calculations, and rather reference the general approaches and guidance in this
field (26). The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task
Force guidance recommends at least 150 subjects per subgroup. The level of precision increases
substantially as sample size increases to 150, with little increase in precision observed as samples
increase beyond 300 participants (26). Sample sizes are to a high degree influenced by the feasibility
of recruitment for this particular type of study. Sample sizes below 100 participants are not uncommon,
in fact, a literature review revealed that 32% of DCEs had a sample size less than 100 participants
(27).
3.3. Participant Recruitment
The target number of sites is approximately seven sites in each European country and ten sites each
in the US and in Canada. Additional centers may be added or substituted if the initial sites are having
difficulties recruiting participants and are unlikely to meet targets.
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18Patient and caregiver dyads will be recruited according to the eligibility criteria specified in Section 3.3.
It is anticipated that not all patients have caregivers. Note that as indicated in section 3.4, only 20% to
40% of the caregivers are expecting to complete the survey. Recruitment will be conducted via sites
using a competitive approach. To ensure a geographical spread among European sites, a single site
will be allowed to recruit up to 18 patients per condition. To ensure a geographical spread among North
American sites, a single site will be allowed to recruit up to 24 patients per condition. Flexibility in going
over those numbers could be given if difficulties are encountered by other sites to meet the recruitment
target.
Sites will identify potential participants based on their medical records, and screen potential patients
for interest and eligibility study-specific screening questionnaire (Appendix A). Sites will also invite
caregivers of patients to participate to the survey.
Site staff will explain in person or over the phone the study to those participants who would have
contacted the site staff to show interest. Site staff will address any questions or concerns participants
may have, and screen them to confirm eligibility using the study-specific screening questionnaire
(Appendix A). The screening results will be tracked locally to facilitate the recruitment of a diverse
sample in terms of key characteristics such as age or sex. The screening results will also be tracked
to monitor the recruitment of both adherent and non-adherent patients, with a target of up to 70% non-
adherent patients. While the target of up to 70% is an optimistic target, efforts are made to enrich the
sample for participants who are not adherent in order to i) address the objectives focused on
understanding barriers to adherence, thus a large enough sample of non-adherent patients is required,
and ii) obtain variation in adherence levels in order to associate it with outcomes. Eligible individuals
will be provided with a copy of the country/site adapted informed consent document (ICD) (see
Appendix B for the master ICD) approved by the local ethics committees. Patients in the US and in
Canada will be asked in the ICD to indicate if they wish to complete the full survey or only the first part
by checking the appropriate option. Sites will manage both the consenting of participants and will also
manage the storage of the consent forms. Only then will the site pass on contact information using the
provided contact order form (Appendix C) to ICON’s Direct-to-Patient Contact (DPC) team to send
remuneration following the completion of the survey, if applicable per local regulation.
While participants will be given by the sites a link to complete the survey online, participants willing to
take the survey via telephone or by paper will inform site staff and will be asked to share their
preference and contact details. The site staff will send the participant contact details to the ICON DPC
team in order for the ICON DPC team to administer the survey by phone or to ship the paper survey
to the participants and remind them to complete it when applicable.
3.4. Study Materials
The following study materials will be used in this study:
● Caregiver and patient screening forms (Appendix A)
● Master ICD (to be customized to meet local requirements; Appendix B)
● Contact order form (Appendix C)
● Final surveys with DCE component (Appendix D)
● eCRF (Appendix E)
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193.5. Study Procedures
Part A of the patient survey will take approximately 30 minutes to complete (including stand-alone de
novo questions and PRO questionnaires) and Part B of the survey will take up to an additional 30
minutes (DCE component). The caregiver survey shall take overall approximately 30 minutes to
complete.
Survey content and completion - A total of four surveys were developed: one for patients and one
for caregivers, for each condition (nAMD and DME). The surveys will ask participants questions about
their disease experience or their experience as caregivers of patients living with nAMD or DME, as well
as treatment-related topics including satisfaction, adherence, and preference (patients only). For that
purpose, the surveys include de novo questions as well as existing PRO instruments/caregiver self-
report measure, and the DCE component (patients only). The final selection of PRO instruments/
caregiver self-report measure was supported by the findings from the qualitative research and include
for patients the standard National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) and a
treatment satisfaction questionnaire (MacTSQ/RetTSQ), and for caregivers the Caregiver Reaction
Assessment. The de novo questions and the DCE component were developed based on the qualitative
research to ensure understanding and relevance of the items. Furthermore, those items and the
instructions were reviewed by patients identified through PAOs to ensure their appropriateness.
A more detailed description of the variables, including the PRO and caregiver self-report instruments,
is available in section 3.6.
To accommodate potential challenges in survey administration due to visual impairment, the surveys
will be available in multiple formats (i.e., paper, online, or via telephone interview) and appropriate font
sizes (where applicable). The following formatting parameters will be implemented to ensure the
optimal comfort for the survey completion:
● No use of italics, however bold text will be used to put an emphasis on a word or part of a
sentence when needed
● Left alignment for the text will be used, no justified alignment
● A font size of at least 14 points but not more than 18 points will be used
● Arial or Verdana font will be used
● White spaces between items and between response options will be integrated
● For the paper version, black text on white background and simple white matte paper will be
used, while for the online version yellow text on black background will be used.
Participants willing to take the survey via telephone or by paper will be asked to share their preference
with the site staff upon recruitment for the ICON DPC team to administer the survey by phone or to
ship the paper survey to their home with a prepaid return envelope, and to remind them to complete it
when applicable.
Participants completing the survey on paper will be asked to return their completed survey via the
provided pre-paid envelope to the ICON DPC team who will perform a check for patient/caregiver
identifiers and forward to the ICON Data Management team who will enter the survey responses into
the EDC.
Specific instructions will be developed on the survey based on the mode of administration (e.g.,
instruction lines, phone script).
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20For participants willing to take the survey by phone interview, the ICON DPC team will call the
participants and administer the survey over the phone. The ICON DPC team will simultaneously enter
the survey responses into the EDC.
Participants willing to take the survey online will receive an email from the ICON Data Management
team with a link to the survey along with their unique credentials to access the survey. On the online
platform, participants will be allowed to leave and re-enter the survey if they are not able to complete
it in one sitting. Participants who save partially completed surveys will be prompted to confirm if they
have finished the survey before leaving the platform; if not submitted. This will trigger up to two
reminder emails to submit the survey. The first reminder will be sent 48 hours after the initial invite, the
second one after a further 72 hours. The survey will finally be closed a week (7 days) after the initial
invite if the participant does not submit it.
Separately, all data extracted from patient medical records will be entered by the sites into eCRFs.
Data extraction will be performed only by site staff who would have received appropriate training and
have access to materials for appropriate eCRF completion. Roche and ICON will not have access to
the participant’s medical records except if in relation to SDV (see section 4.2 for additional details on
SDV) and no identifiable data will be entered on the EDC.
As the site extracts data from the patient records and enters them into the EDC, an anonymous patient
ID will be created. The surveys will be completed under this patient ID in the EDC.
eCRF content and completion
Sites will be asked to extract and enter into the EDC a series of socio-demographic and clinical
questions. Patients’ medical records will be screened to extract information on patient
sociodemographic characteristics, medical history, treatments received including anti-VEGF
treatments, comorbidities, and visual acuity.
A more detailed description of the extracted variables is available in section 3.6.
Remuneration
Participants will be remunerated if allowed and in accordance with local regulations, as specified in
the ICD. The incentive will be paid by prepaid card or voucher, as appropriate.
3.6. Variables and Data sources
Data will be collected through patient and caregiver surveys and patient medical records.
The patient survey (available in Appendix D) has five sections:
● Section 1 asks about the patient’s clinical history and treatment experience through de novo
questions
● Section 2 asks about treatment preferences through a DCE
● Section 3 asks about the patient’s satisfaction with their current treatment using validated
questionnaires (MacTSQ for patients living with nAMD, and RetTSQ for patients with DME)
● Section 4 asks about the patient’s vision-related functioning using the validated NEI-VFQ-25
● Section 5 asks general questions about the patient’s demographic characteristics
The caregiver survey (available in Appendix D) has four sections:
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21● Section 1 asks questions on the caregiver demographic characteristics and relationship with
the care recipient
● Section 2 asks questions about the care recipient’s clinical history and treatment experience
● Section 3 asks about experiences as a caregiver and its impacts
● Section 4 asks about how the caregiver feels about caregiving using the Caregiver Reaction
Assessment scale
Medical records extracted by sites and recorded in the eCRF are described below in Section 3.6.5.
3.6.1. Survey - Participant Characteristics
The following patient characteristics will be collected from surveys completed by the patients:
● Demographic characteristics
o Race/ethnicity, if permitted by local legislations
o Education level
o Marital status
o Living arrangement
o Working status and occupation
o Household income
o Living area (urban/suburban/rural)
o Insurance coverage
● Clinical characteristics
o Symptoms of nAMD/DME
o Smoking status
o Comorbidities
o Health care provider conducting eye examinations
o Prescribed frequency of injections
o Prescribed frequency of monitoring visits
Few patient characteristics including age and gender will be collected in the eCRF, see section 3.6.5.
The following caregiver characteristics will be collected from surveys completed by the caregivers:
● Gender
● Race/ethnicity, if permitted by local legislations
● Level of education
● Marital status
● Working status and occupation
● Household income
● Living arrangement
3.6.2. Survey - De Novo Questions
A series of items were developed to cover aspects related to the ability and willingness of patients to
follow their management plan. Items included:
● Treatment expectations
● Rescheduled and missed injection visits and monitoring visits over the past 12 months
● COVID-19 impact on ability to follow treatment management plan
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22● Factors identified as barriers/obstacles to receiving the injections over the past 12 months
(treatment-related factors, appointment-related, financial-related factors)
● Travel to appointments (mode of transportation, need for an accompanying person, travelling
time)
● Waiting time and appointment duration for injection visits and monitoring visits
● Having a caregiver and being a caregiver
● Financial impact of injections due to transportation, lost wages
● Professional impact of injections, including absenteeism and presenteeism
● Impact of injections on daily activities
Similarly a series of items were developed to cover aspects related to the ability and willingness of
patients to follow their management plan from the caregiver perspectives as well as the impact of
caring on the daily lives. Items included:
● Relation to the care recipient and characteristics of the care recipients
● Clinical history of the care recipient, including treatment management plan
● Rescheduled and missed injection visits and monitoring visits over the past 12 months
● COVID-19 impact on ability to follow treatment management plan
● Factors identified as barriers/obstacles to receiving the injections over the past 12 months
(treatment-related factors, appointment-related, financial-related factors)
● Travel to appointments (mode of transportation, need for an accompanying person, travelling
time)
● Waiting time and appointment duration for injection visits and monitoring visits
● Financial impact on caregiver due to attendance to injections and monitoring visits
● Professional impact on caregiver due to attendance to injections and monitoring visits
● Time spend to provide care and support to the care recipient
3.6.3. Survey - PRO and Caregiver Self-Report Instruments
3.6.3.1. NEI-VFQ-25
The National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) is a questionnaire which was
developed in 1996 to measure the influence of visual impairment on quality of life (28). Several versions
of the questionnaire exist: the original 51-item version, and then two shorter versions with 25 or 17
items (29, 30).
The NEI-VFQ25 is the product of an item-reduction of the longer field test version of the survey, the
51-item NEI-VFQ. It is a standard questionnaire used in numerous clinical trials to assess visual
impairment and its impact on daily activities. The 25 items cover 11 vision-related subscales and one
item on general health. In this study, an additional six appendix items will be included for the Near
Activities and Distance Activities subscales. Each item score is converted to a 0 to 100 scale, and a
mean score per scale can be calculated. Subscale scores include general vision (1 item), ocular pain
(2 items), near activities (6 items), distance activities (6 items), vision-specific social functioning (2
items), mental health (4 items), role functioning (2 items), dependency (3 items), driving (2 items),
peripheral vision (1 item) and color vision (1 item). An overall composite score can also be calculated
by an average of the vision-targeted subscale scores, excluding the general health rating question. A
high score indicates a better vision-related functioning. The NEI-VFQ25 questionnaire has
demonstrated good reliability, validity and ability to detect change (29).
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233.6.3.2. RetTSQ
The RetTSQ was developed to provide a means of evaluating satisfaction with treatment for diabetic
retinopathy (31). The measure was designed along the lines of the widely used Diabetes Treatment
Satisfaction Questionnaire (DTSQ) and sister measures for other conditions. The item content and
layout of the RetTSQ was designed with the use of semi-structured interviews with patients with
diabetic retinopathy of varying degrees of severity following various treatments in the UK and Germany
(31).
This questionnaire consists of 14 items. The first 13 items ask participants to rate various aspects of
treatment with response options ranging on a 7-point Likert scale to rate level of satisfaction where a
score of 6 reflects optimal satisfaction on any one item. The last item invites a free-text response if the
respondent identifies any other aspects of treatment with which they are satisfied or dissatisfied not
covered in the previous 13 questions.
The RetTSQ provides a scale score (range 0-78) and two subscale scores: one providing positive
aspects (based on 7 items, range 0–42) the other one providing negative aspects (based on 6 items,
range 0–36). For all three scores, the higher the score, the greater the satisfaction with treatment.
3.6.3.3. MacTSQ
The MacTSQ was developed to provide a means of evaluating satisfaction with treatment for macular
disease. The measure was designed based on the DTSQ and more particularly based on the RetTSQ
with questions specific to diabetic retinopathy being replaced by items important to patients with
macular disease as informed by 20 one-to-one in-depth interviews with people with AMD (32).
The MacTSQ is a tool of 15 items, with response options ranging on a 7-point Likert scale to rate level
of satisfaction with 0 reflecting the greatest dissatisfaction and 6 the greatest satisfaction favorable
with treatment. Three items were eliminated from the scoring but retained in the questionnaire to be
analyzed separately if required.
The MacTSQ provides a scale score (range 0-72) and two subscale scores: impact of treatment (based
on 6 items, range 0–36) and information provision and convenience (based on 6 items, range 0–36).
For all three scores, the higher the score, the greater the satisfaction with treatment.
3.6.3.4. Caregiver Reaction Assessment
The Caregiver Reaction Assessment is a self-rated burden scale consisting of 24 items representing
5 dimensions of the caregiving situation (impact of caregiving on the caregiver's schedule, impact of
caregiving on caregiver's financial situation, degree of family support, impact of caregiving on
caregiver's health status, and the degree to which the caregiver views on self-esteem) (33). Each item
is answered using a 5-point Likert scale with responses ranging from 1 (strongly agree) to 5 (strongly
disagree). The composite scores are computed as averages of the items within each dimension,
ranging from 1 to 5. Higher scores on the negative dimensions represent higher levels of perceived
burden (the exception to this is the self-esteem scale).
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243.6.4. Survey – DCE Component
DCEs are a quantitative survey method that allow the estimation of the relative strength of preferences
for the attributes of a treatment. In the current DCE component of the patient survey, hypothetical
treatment choice scenarios (choice tasks) are presented to the participant, who is asked to select which
they prefer, and if they would be likely to adhere to that treatment plan. The treatments in the choice
tasks are characterized by five attributes, each having two to four levels. The attributes and level
included in the DCE are outlined below (the details of the attributes and levels are given in Section 2
of the patient survey in Appendix D):
● Mode of administration (Injections / Implant surgery and refills)
● Frequency of monitoring visits (every 1 month / 2 months / 3 months / 4 months)
● Frequency of injections/refills (every 1 month / 2 months / 4 months / 6 months)
● Likely change in visual acuity (Stabilization/ Slight improvement/ Meaningful improvement)
● Eye-related side effects (Mild-moderate, frequent/ Severe, rare)
The choice of attributes and levels was informed by the literature, interviews with payers, PAOs,
patients, HCPs, and discussions with the study initiator. Feedback on the relevance and
appropriateness of the initial design of the DCE component was gathered from nAMD or DME patients
identified through PAOs, and following this the DCE was finalized. The DCE will consist of
approximately 30 choice tasks. However to minimise patient burden, three blocks of up to 10 choice
tasks each will be created. Blocks are equally sized partitions of the choice tasks. Patients will be
randomly assigned to a block and answer the choice tasks in that block instead of answering all choice
tasks. The DCE component starts with instructions, and detailed descriptions of the attributes and
levels, before progressing to an example choice task, and then up to 10 choice tasks for data collection.
The DCE component concludes with four questions evaluating the relevance and the ease of
comprehension of the choice tasks.
3.6.5. eCRF
The below patient information will be retrieved from health records and entered into the eCRF:
● Age
● Gender
● Visual acuity (including baseline) in both eyes with scale (ETDRS, Snellen, logMAR etc.) and
type of correction (best-corrected, habitual correction, etc.)
● Condition (DME or nAMD)
● Unilateral or bilateral condition
● Type of macular degeneration (neovascular 'wet', non-neovascular 'dry’)
● Presence of geographic atrophy
● Presence of disciform scarring/ fibrosis
● Relevant ocular comorbidities (retinal vascular disease, other macular pathology, glaucoma
or optic neuropathy, amblyopia, or medial opacity in affected eye, previous cataract surgery,
YAG laser capsulotomy, vitrectomy, corneal surgery, previous endophthalmitis/panuveitis)
● COVID-19 infection prior to screening date
● Type of treatment(s) (e.g., anti-VEGF injection, laser therapy, corticosteroid injections or
implants) with if available, date of therapy switch and rationale
● Prescribed treatment regimen/management plan (monitoring and injection visit intervals)
● Actual treatment dates/number of treatments in the past year
● Reasons for missed visits (if available)
MR41928 Protocol, Version 1.0, 20 October 2020
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