Patient Reported Outcomes Burdens and Experiences - Phase 2 - Pilot Feasibility Study
Conditions: Hemophilia
Sponsor: McMaster University

PATIENT REPORTED OUTCOMES BURDENS AND 
EXPERIENCES STUDY (PROBE): A PRO TOOL 
DEVELOPMENT INITIATIVE  
 
 
NCT02439710 
28 June 2016 
 
 
 

 
TABLE OF CONTENTS 
PROTOCOL FINALIZATION SIGNATURE PAGE .............................................................. 2 
1. 
LIST OF ABBREVIATIONS ................................................................................. 5 
2. 
SYNOPSIS................................................................................................................ 6 
3. 
PROTOCOL AMENDMENTS AND UPDATES ........................................................... 8 
4. 
RATIONALE AND BACKGROUND ........................................................................... 9 
4.1 
Study Rationale ............................................................................... 10 
5. 
RESEARCH QUESTION AND OBJECTIVES .........................................................11 
5.1 
Research Question ..........................................................................11 
5.2 
Objectives ....................................................................................... 11 
6. 
RESEARCH METHODS ......................................................................................... 12 
6.1 
Study Design ................................................................................... 12 
6.1.1 
Overview of Study Design............................................................... 12 
6.1.2 
Rationale for Study Design ............................................................. 14 
6.1.3 
Number of Subjects Observed in the Study ................................... 14 
6.1.4 
Sites ................................................................................................ 14 
6.2 
Population ....................................................................................... 14 
6.3 
Variables ......................................................................................... 14 
6.4 
Data Sources .................................................................................. 14 
6.4.1 
Data Collected during the Observation Period ............................... 15 
6.4.2 
Data Collected at Study Completion ..................................................15 
6.5 
Subject, Study, and Site Discontinuation ....................................... 15 
6.5.1 
Subject Discontinuation .................................................................. 15 
6.5.2 
Withdrawal from Study.................................................................... 15 
6.5.3 
Study and Site Discontinuation ..........................................................15 
6.6 
Data Management .......................................................................... 16 
6.7 
Statistical Considerations ............................................................... 16 
6.7.1 
Primary Objective Analyses .............................................................. 16 
6.7.2 
Timing of Analyses ..........................................................................16 
6.7.3 
Determination of Sample size .........................................................16 
6.7.4 
Study Documentation………………………………………………….17 
6.7.5 
Site Audits and Inspections .............................................................17 
6.7.6 
Administrative Structure .................................................................... 17 
6.8 
Limitations of the Research Method ................................................17 

 
7. 
PROTECTION OF HUMAN SUBJECTS................................................................... 17 
7.1 
Compliance with Laws and Regulations ............................................ 17 
7 .2 
Informed Consent. ............................................................................ 17 
7 .3 
Institutional Review Board or Ethics Committee ............................... 18 
7 .4 
Confidentiality ................................................................................... 18 
8. 
MANAGEMENT OF ADVERSE EVENTS ................................................................ 19 
9. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS ............................................................................................................... 20 
1 0. 
REFERENCES.........................................................................................................21 
 
 
LIST OF APPENDICES 
 
Appendix 1 
Study Investigators .................................................................................. 3 
 
 

1. 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
BU 
Bethesda Units 
CDC 
Centre for Disease Control (US) 
CEO 
Chief Executive Officer 
CVAD 
Central Venous Access Devices 
EC 
Ethics Committee 
FVIII 
Factor Eight 
HIPAA 
Health Insurance Portability and Accountability 
Act (US) 
HRQol 
Health Related Quality of Life 
ICC 
Intraclass Correlation Coefficients 
IV 
Intravenous 
aPCC 
activated Prothrombin Complex Concentrates 
PRO 
Patient Reported Outcomes 
PROBE 
Patient Reported Outcomes, Burdens, and 
Experiences 
SC 
Subcutaneous 
SAE 
Serious Adverse Event 
 

 
2. 
TITLE: 
 
SYNOPSIS 
 
 
 
 
PATIENT REPORTED OUTCOMES BURDENS AND 
EXPERIENCES STUDY [PROBE]: A PRO TOOL 
DEVELOPMENT INITIATIVE 
PROTOCOL NUMBER:  
VERSION NUMBER:  
DATE OF SYNOPSIS: 
STUDIED MEDICINAL 
PRODUCT: 
INDICATION:  
 
STUDY INITIATOR: 
 
MAIN AUTHOR: 
MO39306  
2,0 
28 June 2016  
None 
 
Haemophilia 
 
+1 2022 961351 
 
Mark Skinner 
 
 
 
 

Research Question and Objectives Objectives 
The primary objective for this study is to validate a PRO instrument for quantifying 
burden of disease of haemophilia globally. 
Study Design 
Test-retest study of PRO instrument. Study 
timeline. 
First quarter 2016 - Finalize protocol, study questionnaire, website development and 
related field work materials. 
• 
Second - Fourth quarter 2016 - Country recruitment and begin sampling exercises. Field 
work anticipated to begin by March 1, 2016 and complete by year-end. Two sampling exercises 
will be conducted in each country within six months. 
• 
Fourth quarter 2016 - Conduct statistical analysis & project evaluation. Analyze 
individual country results and assess reproducibility. Evaluate project. Study results will be 
submitted for publication soon thereafter. 
Target Population 
Haemophilia patients and a control population, from around 6 difference countries. 
Variables 
Primary Outcome 
- Feasibility, measured 
as: 
• 
Response rate 
• 
Percent complete responses 
• 
Time to completion 
• 
Cost per completed survey 
Data Sources 
Data will be captured on either web or paper based questionnaire,  and transferred t a central 
database for analysis. 
Data Analysis 
Descriptive statistics will include the mean of the aggregated scores, the standard deviation 
and the mean difference between the scores of the first and second questionnaire. 
Agreement will be assessed using intraclass correlation of Spearman's rank correlation 
coefficient at the level of individual items and for each composite domain. 
Study Size/Determination of Sample Size 
In this study approximately 75 subjects will be enrolled across 6 countries. 
 
 
 
 
 
 
 

 
3. 
PROTOCOL AMENDMENTS AND UPDATES 
Any protocol amendments will be prepared by the study initiator. 
The Scientific Responsible will seek Counsel / Consultancy for the Protocol and 
succeeding amendments with his/her competent Ethics Committee. 
Protocol amendments/updates so far: none 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 

 
4. 
RATIONALE AND BACKGROUND 
Haemophilia A is an X-linked recessive bleeding disorder due to congenital underproduction or 
dysfunction of the essential coagulation factor VIII (FVIII). The incidence of haemophilia A is 
approximately 1 in 5,000 live born males, without racial differences, and it accounts for 
approximately 80% of all cases of haemophilia (Centers for Disease Control and Prevention 
(CDC) 2014; National Institutes of Health [NIH] 2014; Franchini and Mannucci 2013; World 
Federation of Hemophilia [WFH] 2013). 
Haemophilia A is a lifelong bleeding tendency, and its severity depends on the residual FVIII 
activity. Approximately 40% of patients have severe (<1% FVIII activity) disease 
characterized by spontaneous bleedings. Bleeding sites include intra articular, 
intramuscular, subcutaneous (SC), gastrointestinal, mucocutaneous, and intracranial. 
Haemophilia A is characterized by recurrent joint bleeds resulting in debilitating joint 
damage, pain, and limited range of motion. This haemophilic arthropathy has a major 
impact on health-related quality of life (HRQol) and patients often require surgical 
intervention, including joint replacement at a young age. 
The mainstay of treatment for haemophilia A is replacement of FVIII by recombinant (rFVIII) 
or plasma derived FVIII concentrates. Intravenous (IV) infusion of these products restores 
hemostasis, albeit temporarily due to a short half life of 8-12 hrs. Approximately one third of 
patients develop allo antibodies (inhibitors) against FVIII, and high titer inhibitors (? 5 
Bethesda units [BU]/ml) result in neutralization of endogenous or exogenous FVIII. These 
patients may be treated with bypassing agents (e.g. recombinant FVlla  [rFVlla] or activated 
prothrombin complex concentrates [aPCC]). 
These products restore hemostasis less reliably, have shorter half-lives, and are associated 
with severe adverse events (AEs), including thromboembolism. Thus, patients with inhibitors 
have markedly increased risk of morbidity and mortality (Franchini et al. 2012). 
Factor replacement may be given to treat a bleed (i.e., episodic, on demand) or as routine 
prophylaxis to prevent bleeds by maintaining FVIII level above 1%. With appropriate 
prophylaxis, nearly half of patients do not bleed spontaneously whereas episodic treatment 
may be associated with several bleeds each month (Srivastava et al. 2013). Therefore, 
prophylaxis is superior to episodic treatment (Khawaji et al. 2012) and has been adopted by 
national and international organizations as the desired treatment approach. However, the 
burden of treatment (Eton et al. 2013, Mair and May 2014) is extraordinarily onerous, as 
adequate prophylaxis requires a lifetime of self-administered IV infusion of FVIII 3 4 times each 
week. In addition, routine IV FVIII therapy relies on venous cannulation skills of patients and 
their care providers (Hacker et al. 2001). In particular, this issue plagues the care of children 
and the elderly, often requiring central venous access devices (CVADs [i.e., port a cath]). 
Although CVADs make prophylaxis feasible, they are associated with complications, including 
mechanical failure, infection, and thrombosis (Leissinger et al. 201Sa; Leissinger et al. 
2015b). Thus, both the 
 
9 

 
disease and its treatment affect patients' HRQoL. In addition to the obvious toll on the 
quality of patients' lives (Teal et al. 2014), the burden of treatment results in suboptimal care 
for many who elect to avoid routine prophylaxis or cannot comply with the demanding 
prophylactic regimen, despite its medical advantage (Geraghty et al. 2006; Lindwall et al. 
2006; De Moerloose et al. 2008; Collins et al. 2014; Oldenburg 2015). 
Given the unmet need in haemophilia, the disease presents a high burden to patients. It is 
important that this burden is quantified and appreciated. 
4.1 
STUDY RATIONALE 
Research based on patient-centered datais increasingly valued by government and 
private payers and utilized in public-policy decisions as part of 
the cost-benefit 
justification 
for high-cost careand treatment. A frequent question of payers is: Will 
additional investment (to sustain or expand care) improve the livesof persons with 
hemophilia? There is a significant need to improve our ability to collect, collate, and 
interpret relevant patient-centered data to support the implementation of comprehensive 
care, home treatment and preventative treatment regimens (e.g., prophylaxis). 
The PROBE study is intended to fill this gap and enhance the direct patient-voice in the 
delivery of care  and move advocacy efforts to sustain and expand carebeyond emotion 
to arguments grounded in evidence and data. 
The overall inventory and the specific metrics developed through PROBE would complement 
the existing global comparative metrics of the World Federation of Hemophilia (WFH) as 
provided in the WHF Global Survey (e.g., the percent of patients identifiedvs. expected within a 
country, amount of treatment products availablewithin a country on a per 
capita basis, and the ratioof children to adults survivinginto adulthood). While the WFH global 
metrics are valued and useful, theydo not provide a complete  or direct insight as to how 
patients are fairing within theirhealth caresystem. The existing WFH metrics only serve as proxy 
measures of the impact of careon patient outcomes within a country. 
PROBE has an integrated knowledge translation component. Thiscomponent will be 
manifested through the development and validation of an inventory ableto recode experiential 
datacontributed by patient organizations to a 
valid foundation for evidence-based decision making (e.g.within Health Technology 
Assessments[HTAs]). PROBE will alsobe useful in raising awareness within the 
community and the public of the impact of treatment for persons living with hemophilia 
(PWH) and the value of effective prevention. 
 
 

 
5. 
RESEARCH QUESTION AND OBJECTIVES 
5.1 
RESEARCH QUESTION 
The Patient Reported Outcomes, Burdens, and Experiences (PROBE} Study aims to develop a 
new global tool to enhance the direct patient-voice in health care decision- making. Government 
and private payers increasingly value data based on patient- centered outcomes research as part 
of the overall cost-benefit evaluation of high-cost care and treatment of diseases such as 
haemophilia. 
This emerging dimension of the healthcare environment presents a significant opportunity and 
urgent need to improve patient organizations' ability to collect and interpret relevant outcomes 
data. More robust patient reported data will improve advocacy efforts to build comprehensive 
care programs, promote home treatment and implement preventative treatment regimens thus 
allowing advocacy arguments to move beyond emotion and anecdote to those grounded in real-
world patient experiences and evidence. 
With the support of the National Hemophilia Foundation, a global team of investigators will lead 
a patient focused research project to investigate and directly probe patient perspectives on 
outcomes they deem relevant to their care. 
Through PROBE we will develop and seek to validate the reliability, reproducibility and 
responsiveness of a low cost, easily administrable inventory for collecting patient self-reported 
outcomes, burdens and experiences in living with hemophilia. We anticipate that the metrics 
established through PROBE will allow for comparison of patient outcomes within a country over 
time and cross-sectionally between countries (regionally and globally}. 
5.2 
OBJECTIVES 
The focus of PROBE will be to investigate and directly probe patients perspectives on 
outcomes they deem relevant to their care. Through PROBE, we will develop to validate the 
reliability, reproducibility and responsiveness of a low-cost, easily administrable inventory for 
collecting patients self-reported outcomes, burdens and experiences in living with hemophilia. 
PROBE will be conducted as a multipart study with three Phases. The primary objectives of each 
phase are distinct but interrelated in their design and funding. They build upon each other in an 
iterative manner. 
This phase, Phase 2, is a pilot feasibility to validate the proof of concept, assess 
reproducibility and practicality of developing an inventory for large-scale assessment of patient-
centred outcomes in people with haemophilia. We expect to be able to compare the effect of 
different treatment deliver modalities and regimens on patient outcomes. 
We anticipate that the metrics established through Phase 2 will allow for comparison of patient 
outcomes within a countries over time and cross-sectionally between countries (regionally and 
globally}, thus providing an important new tool to sustain and promote additional health care 
investment. 
 
11 

6. 
RESEARCH METHODS 
6.1 
STUDY DESIGN 
6.1.1 
Overview of Study Design 
This study will seek to validate a previously developed PRO instrument, using the principles 
below. 
Step I. Developing a draft inventory. Building upon the work of Phase 1, an inventory 
consisting of a composite self-administrable questionnaire will be developed during an in-
person meeting of the Investigators. The inventory will bundle the EQ-5D-5L instrument 
along with supplemental questions covering additional domains assessing the impacts of 
hemophilia on a PWH's life (e.g., pain, independence, educational attainment, employment, 
activities of daily living) into an integrated questionnaire. The EQ-5D-5L will not be altered. 
Demographic and treatment related information will be collected for comparison and 
analysis (Step IV) but not included in the inventory. Where feasible, we will incorporate 
generic instruments that are already widely accepted by public policy makers. 
Step II. Field testing and finalizing the draft inventory. The prototype will be tested for face validity 
(i.e., the extent to which the inventory covers the concepts and content purported to be covered 
will be addressed in-depth within the Phase 1 workshop), clarity, and for the time needed for use 
via one-to-one interviews and user testing with volunteer patients until stable. We will use 
standard qualitative technology for scale development. Supplemental validity testing will be 
undertaken as determined necessary following the workshop debrief and based on PROBE Study 
5 additional countries recruited for Phase 2 (e.g., those not participating in the Phase 1 
workshop). Whether this will occur in country, via focus group, telephone consultation or third-
party has not been pre- determined. 
Step Ill. Country Recruitment. The final group of countries selected for the PROBE Phase 2 
pilot feasibility study will draw upon the Summit participants. Additional developing and mid-tier 
countries will be recruited. The final group of countries for the pilot feasibility assessment will 
be selected to ensure a diversity of geography (e.g., North America, Asia, Africa, Europe, Latin 
America), economic and care development levels are represented. In total, up to six countries 
will be invited to participate in Phase 
2. Initial expressions of interest or targets to participate have been identified from a range of 
countries / regions of the world (e.g. Australia, Canada, Denmark, Kenya, India, Ireland, South 
Africa, US, Vietnam). Recruitment for Phase 2 will begin following launch of Phase 1 and the 
Barcelona workshop. Resource limitation in Phase 2 design will not allow every possible country 
combination to be included in the Pilot phase, but PROBE will endeavor to have a diverse 
country mix. No compensation is contemplated for individual PWH study participants. 
Additionally, although not contemplated in the budget proposal, reimbursement for associated 
stdy costs of participating country patient organizations would be considered if required. 
Step IV. Test run. Two moderate to large test runs of the inventory will be conducted in each 
country three months apart to demonstrate reproducibility (Approximately 600 PWH in total - 
50 PWH per sampling exercise x six countries x two test runs per country). Both paper and 
web versions will be developed with translations as required. PWH will be recruited for 
participation via patient organization contact database and their social media portals. 
Reproducibility will be assessed based on an analysis of 
 
12 

 
amount of variability within and across sampling exercises with each country. 
Responsiveness will be assessed based on response rate and percent complete responses. 
Reliability will be demonstrated by a combined assessment of measurements for the primary 
outcomes of Phase 2 (e.g. response rate, complete responses, agreement between exercises, 
duration, cost and feasibility of execution.) (See: Primary Outcome Variables / Measurement Of 
Results section below). 
Step V. Analysis. The data will be collected at the individual level, but responses will be de-
identified and aggregated to perform comparison of outcomes at the population level rather than to 
allow comparison of outcomes at the individual patient level. We plan to perform three 
comparisons: among countries, within country over time, within country against national normative 
data. We will preliminarily assess if normative data are available for the domains explored via 
existing instruments. When normative data are not available, we will consider strategies to 
produce a comparator (e.g. surveying non- effected siblings). We will also explore suitable data 
from other chronic conditions to support the aim of the study. We will conduct a sensitivity analysis 
to assess the sufficiency of the inventory to measure changes on the impact of care within 
populations of PWH or overtime using data collected from disease specific questions in the 
PROBE questionnaire in combination with the EQ-SD. A centralized data collection point will be 
established. Initial data compilation and cleaning of the database will be incorporated within the 
web-platform development and reporting agreement (e.g. McMaster University). An analyst 
experienced in analysis of EQ-SD data and the related study domains will conduct an initial 
analysis. The Investigators will then evaluate the data and determine the final comparisons and 
correlations for analysis. Supplemental analyses, data correlation and reporting will utilize/ be 
contracted for with a university biostatics or health outcomes department experienced in similar 
studies (e.g. McMaster University, University of Southern California, North Carolina State 
University). 
The specific FDA guidance on Patient Reported Outcomes (FDA, 2009) will be followed. In 
general, a test-retest experiment is most informative when the time interval chosen between 
the test and retest is long enough in stable patients to minimize memory effects. However, the 
choice of the time interval has to take into account the variability of the disease or experience 
being evaluated (e.g. the potential for change in the condition 
over time). In other words, the test-retest experiment is intended to explore than variability in 
stable patients, and is biased by actual changes in the condition. The FDA guidance 
acknowledges that "for remitting and relapsing or episodic diseases, test-retest reliability may be 
difficult or impossible to establish." Therefore, the test-retest reliability can be tested over a 
variety of periods to satisfy different study protocols or even in different intervals between 
visits in the same protocol. Examples in the musculoskeletal field span from intervals between 
the two tests of minutes to several months (Stratford et al, 2007; Whitehouse et al, 2003; Yang 
et al, 2007; Theiler et al, 2002). 
Similarly, the sample size for the test-retest study is usually defined, when the measurement 
properties of the instrument under study are known, by calculating the number of subjects 
needed to exclude a pre-specified variability. This is almost invariably the case when the test-
retest experiment involves a pre-validated instrument used in a different setting or modified or 
translated. For new instruments, empirical sample sizes, usually from 25 to 100 subjects, and 
two or more replicates are used. 
Study timeline. 
 
 
13 

• 
First quarter 2016 - Finalize protocol, study questionnaire, website development and 
related field work materials. 
• 
Second - Fourth quarter 2016 - Country recruitment and begin sampling exercises. 
Field work anticipated to begin by March 1, 2016 and complete by year-end. Two 
sampling exercises will be conducted in each country within six months. 
• 
Fourth quarter 2016 - Conduct statistical analysis & project evaluation. Analyze individual 
country results and assess reproducibility. Evaluate project. Study results will be 
submitted for publication soon thereafter. 
6.1.2 
Rationale for Study Design 
Prior phases of the study included development and testing a paper questionnaire for 
content, relevance, clarity and completeness, as well as assessing methodology and 
feasibility. This pilot questionnaire was updated for this phase of the PROBE study and 
has also been adapted to a web-based format. 
6.1.3 
Number of Subjects Observed in the Study 
The study will aim to recruit at least 75 participants in each of 6 countries.  
6.1.4 
Sites 
This study will be conducted in approximately 6 countries. 
Additional countries and centers may be added or substituted if underperforming.  
6.2 
POPULATION 
Patients will haemophilia will be invited to participate in the study. Additionally, 
participants without bleeding disorders will also be asked to participate as a control 
group. 
Participation will be voluntary and data collected anonymously. Subjects will be recruited 
by the national (or a sub-national e.g. state or chapter) patient organization in the 
country. Subjects do not need to be the same people in each sampling exercise, but 
generally the same make-up of people (e.g. members of the patient society). 
6.3 
VARIABLES 
Reproducibility will be assessed based on an analysis of amount of variability within and 
across sampling exercises with each country. Responsiveness will be assessed based 
on response rate and percent complete responses. Reliability will be demonstrated by a 
combined assessment of measurements for the primary outcomes of Phase 2 (e.g. 
response rate, complete responses, agreement between exercises, duration, cost and 
feasibility of execution.) 
6.4 
DATA SOURCES 
PROBE Tool 1- Phase 2 Final 
 
 
14 

 
6.4.1 
Data Collected during the Observation Period 
Participants will be asked to fill out the questionnaire objectively answering the questions for 
themselves. If completed on paper, the questionnaires will be collected by the patient 
organization, if by web, the data will be received directly into the PROBE database. 
Paper files will be centrally input to the database. Participants will complete the questionnaire in 
their local language. 
Patients will be asked to complete the PRO tool independently of their physician or usual care 
practice. Thus, no study-specific visits or evaluations are required by this protocol. 
6.4.2 
Data Collected at Study Completion 
Data will be collected from the PRO tool only. 
6.5 
SUBJECT, STUDY, AND SITE DISCONTINUATION 
6.5.1 
Subject Discontinuation 
Patients have the right at any time and for any reason to withdraw their consent that their data 
are collected and used for the study. Reasons for discontinuation of treatment with the 
medicinal product or withdrawal from the study may include, but are not limited to, the 
following: 
• 
Patient withdrawal of consent at any time 
• 
Patient is lost to follow-up. 
6.5.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the study. 
The primary reason for withdrawal from the study should be documented on the appropriate 
form. Patients will not be followed for any reason after consent has been withdrawn. 
6.5.3 
Study and Site Discontinuation 
The study initiator has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, the following: 
• 
Patient enrollment is unsatisfactory 
The study initiator has the right to replace a site at any time. Reasons for replacing a site 
may include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with any other pertinent local law or guideline 
 
 
15 

 
6.6 
DATA MANAGEMENT 
The study initiator will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the system. 
6.7 
STATISTICAL CONSIDERATIONS 
6.7.1 
Primary Objective Analyses 
Descriptive statistics will include the mean of the aggregated scores, the standard deviation 
and the mean difference between the scores of the first and second questionnaire. Agreement 
will be assessed using intraclass correlation of Spearman's rank correlation coefficient at the 
level of individual items and for each composite domain. 
We will further explore the test-retest reliability of PROBE by calculating Lin's concordance 
correlation (Lin, 1989) coefficient (pc) for both the complete questionnaire and its items 
separately. This indicates how well a pair of measurements conforms to, or deviates from, a 
straight line and determines the degree of agreement, i.e. the extent to which the observations 
conform to a 45° line in a scatter plot when the answer to the first compilation are plotted 
against those of the second one. 
We will use Bland and Altman plots (Bland & Altman, 1986, 2003, 1995) to compare the two 
replicates and calculate agreement limits. 
Finally, we will perform a randomized block analysis of variance and calculate patient and 
residual error variance components. These variance components will be used to calculate 
Shrout and Fleiss (Shrout & Fleiss)Type 2,1 intraclass correlation coefficients (ICC2,1 . 
patient variance/total variance). We will also calculate the SEM as SEMTRT equal to the 
squared root of the residual variance (Stratford, 2004). Error estimates for score values will 
be obtained by multiplying SEMs based on test-retest by 1.65, the Z- value associated with a 
two-sided 90%confidence interval. Minimal detectable change at a 90% confidence level will 
be calculated as follows: SEMTRT x 1:65 x square root of 2 (Beaton et al, 2002; Beaton, 
2001). The square root of 2 term acknowledges two measurements are being compared and 
the value 1.65 is the Z-value associated with a two-sided 90% confidence interval. The 
interpretation of minimal detectable change (MDC90) is that 90% of stable patients will 
display random fluctuations equal to or less than this value when assessed on multiple 
occasions. 
6.7.2 
Timing of Analyses 
Analysis will be conducted at the end of the study only. No interim analyses are planned. 
6.7.3 
Determination of Sample size 
We will assess the test-retest properties of PROBE in countries on a different sample of 
patients and controls (individuals who do not personally have a bleeding disorder) from the 
same country. The test will be administered on paper or via the PROBE website on two 
separate occasions within a time period short enough not to expect meaningful 
 
16 

variation in the provision of care (e.g. six months}. To this scope we have planned to perform two 
PROBE measurements at a distance of about six months in six different countries. To be sure to 
obtain 50 full sets of replicates of which at least 25 will be patients, we will enroll in the study up 
to 75 subjects. Additional countries may be enrolled to be sure we have 6 complete country 
sample pairs. 
6.7.4 
Study Documentation 
The country investigators must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol amendments, 
Informed Consent Forms, and documentation of any necessary authority/committee approval or 
notification. 
6.7.5 
Site Audits and Inspections 
Not applicable 
6.7.6 
Administrative Structure 
The study investigators, listed in Appendix 1, will approve all aspects of study conduct, 
including protocol deviations and amendments, analysis planning and dissemination of results. 
6.8 
LIMITATIONS OF THE RESEARCH METHOD 
The study will be a validation of the previously developed PRO tool. This evaluation is designed 
to demonstrate reproducibility, reliability, and patient response. It is not designed to specifically 
measure the overall burden of the disease in this phase of the study. 
7. 
PROTECTION OF HUMAN SUBJECTS 
7.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the laws and regulations of the country in 
which the research is conducted. 
7.2 
INFORMED CONSENT 
The study initiator's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Assent or Caregiver's Informed Consent Form, 
if applicable} will be provided to each site. 
The Consent Forms must be signed and dated by the subject or the subject's legally authorized 
representative before start of documentation of his or her data in the questionaire. 
By signing the form, the subject confirms that he/she has been informed about the study and 
agrees to pseudonymous data collection, pooling of data with similar scientific data (if 
applicable}, and the possibility of monitoring activities. It is the responsibility of the 
 
17

physician to obtain written informed consent from each subject participating in the study, after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study. The investigator must also explain that the subject is completely free to refuse to enter 
the study or to withdraw from it at any time, for any reason and without losing the benefit of any 
medical care to which the subject is entitled or is presently receiving. 
A copy of each signed Consent Form must be provided to the subject or the subject's legally 
authorized representative. All signed and dated Consent Forms must remain in each 
subject's study file or in the site file and must be available for verification by study monitors at 
any time. 
For sites in the United States, each Consent Form may also include subject authorization to 
allow use and disclosure of personal health information in compliance with the U.S. Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a separate 
Authorization Form for subject authorization for use and disclosure of personal health 
information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRS review and approval may 
not be required per study site policies. 
7.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
The principal investigator will ensure that the protocol receives approval from any relevant 
authority or committee in each of the study countries. 
7.4 
CONFIDENTIALITY 
The study initiator maintains confidentiality standards by coding each subject enrolled in the 
study through assignment of a unique subject identification number. This means that subject 
names are not included in datasets that are transmitted to any study initiator's location. 
Subject medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the Informed Consent Form (or separate authorization for use and 
disclosure of personal health information) signed by the subject, unless permitted or required by 
law. 
Medical information may be given to a subject's personal physician or other appropriate 
medical personnel responsible for the subject's welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, marketing authorization holder 
monitors, representatives, and collaborators, and the IRS/EC for each study site, as 
appropriate. 
 
 
18 

 
8. 
MANAGEMENT OF ADVERSE EVENTS 
Although it is not anticipated that the PROBE Study Team will receive reports of Adverse Events 
(AE) / Serious Adverse Events (SAE) within the scope of the Study, if the Investigators are 
made aware of an AE / SAE involving a product manufactured by a study sponsor through the 
conduct of the study, the Investigators commit to notify sponsor within one (1) business day of 
actually becoming aware of any significant product complaint, unexpected adverse event, or 
governmental investigation or inquiry involving a sponsor's product. Study questionnaire may 
not be reviewed in "real-time." It is understood the study questionnaires may be collected but not 
reviewed or entered into the PROBE database until the completion of an individual country 
sampling exercise. 
All study data received by PROBE is de-identified and anonymously reported by individual 
survey participants. The study questionnaire does not allow for identification of individual 
respondents. No product names are mentioned in the study nor is product specific data being 
requested from participants. 
Although unlikely, there are open text fields where it is theoretically possible that a participant 
could enter free text that would mention a treatment product by name and directly associate it with 
a AE/SAE.  E.g.: 
• 
Q.8 
In the past 12 months, have you experience any problems related to your health? 
• 
Q 24. 
Please give a brief history of your treatment regimens during your lifetime (e.g., no 
treatment, on demand with cryo, immune tolerance, regular prophylaxis with factor, on 
demand with factor). 
To the extent possible, PROBE will report the following details: Date 
• 
Country 
• 
Gender Hemophilia type 
• 
Hemophilia severity Year of 
birth 
• 
Particulars of the AE/SAE - e.g., product name referenced, associated AE/SAE reported and 
the context in which it was reported within the study questionnaire 
 
 
19 

PROBE investigators will cooperate and provide a timely response to any request for additional 
or clarifying information. Investigators will comply with safety reporting requirements pursuant to 
applicable local laws and regulations in the country/countries where the study is being 
performed. 
 
 
9. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
Regardless of the outcome of a study, the study initiator is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The study initiator will comply with all requirements 
for publication of study results. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator must agree to submit all manuscripts or abstracts to the study initiator 
prior to submission for publication or presentation. This allows the study initiator to protect 
proprietary information and to provide comments based on information from other studies that 
may not yet be available to the physician. 
In accordance with standard editorial and ethical practice, study initiator will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In this 
case, a coordinating physician will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors' authorship requirements. Any formal publication of the study in which 
contribution of the study initiator personnel exceeded that of conventional monitoring will be 
considered as a joint publication by the physician and the appropriate study initiator's personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of data from this study will become and remain the exclusive and unburdened property of the 
study initiator, except where agreed otherwise. 
We plan to discuss the study results in an end-of-study meeting. A paper will be submitted to 
Haemophilia summarizing the research findings. Abstracts, posters and requests for oral 
presentation will be considered for relevant national, regional and international meetings 
(e.g., EAHAD, EHC, ISPOR, ISTH, NHF, and WFH). Study participants will be anonymously 
acknowledged for their participation. We will report the research findings to the participating 
patient organizations and once validated PROBE will establish a mechanism to make the 
inventory widely available for use within the hemophilia community (as Phase 3 of the 
project). 
 
 
20 

 
10. 
REFERENCES 
Beaton, D. (2001) A taxonomy for responsiveness. Journal of Clinical Epidemiology, 54, 1204-
1217. 
Beaton, D.E., Boers, M. & Wells, GA (2002) Many faces of the minimal clinically important 
difference (MCID): a literature review and directions for future research. Current Opinion in 
Rheumatology, 109-114 Available at: http://journals.lww.com/co- 
rheumatology/Abstract/2002/03000/Many_faces_of_the_minimal_clinically_important.6.a spx 
[Accessed November 2, 2015]. 
Bland, J.M. & Altman, D.G. (1986) Statistical methods for assessing agreement between two 
methods of clinical measurement. Lancet, 1, 307-10. 
Bland, J.M. & Altman, D.G. (1995) Comparing methods of measurement: why plotting difference 
against standard method is misleading. Lancet, 346, 1085-7. 
Bland, J.M. & Altman, D.G. (2003) Applying the right statistics: analyses of measurement studies. 
Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound 
in Obstetrics and Gynecology, 22, 85-93. 
Centers for Disease Control and Prevention (CDC). Hemophilia Data &Statistics. Accessed April 
22, 2014; http://www.cdc.gov/ncbddd/hemophilia/data.html. 
Cohen, J. (2013)Statistical Power Analysis for the Behavioral Sciences Elsevier Science. 
Collins PW, Young G, Knabe K, et al. Recombinant long-acting glycoPEGylated factor IX in 
haemophilia 8: a multinational randomized phase 3 trial. Blood 2014;124:3880-6. 
Cronbach, L.J. & Warrington, W.G. (1951) Time-limit tests: Estimating their reliability and degree 
of speeding. Psychometrika, 16, 167-188. 
De Moerloose P, Urbancik W, Van Den Berg HM, Richards M. A survey of adherence to 
haemophilia therapy in six European countries: results and recommendations. 
Haemophilia 2008;14:931-8. 
Eton DT, Elraiyah TA, Yost KJ, et al. A systematic review of patient-reported measures of 
burden of treatment in three chronic diseases. Patient Relat Outcome Meas. 
2013;5:4:7-20. 
Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013;179- 
84. 
Geraghty S, Dunkley T, Harrington C, et al. Practice patterns in haemophilia A therapy - global 
progress towards optimal care. Haemophilia 2006;12:75-81. 
 
21 

Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prohylaxis therapy in 
haemophilia. Haemophilia 2001;7:392-6. 
Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult patients 
with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life. Eur J 
Haematol 2012;88:329-35. 
Leissinger CA, Konkle BA, Antunes SV. Prevention of bleeding in hemophilia patients with 
high-titer inhibitors. Expert Rev Hematol. 2015;8:375-82. 
Leissinger CA, Singleton T, Kruse-Jarres R. How I use bypassing therapy for 
prophylaxis in patients with hemophilia A and inhibitors. Blood. 2015;126:153-9. 
Liang, M.H., Fessel, A.H. & Larson, M.G. (1990) Comparisons of five health status instruments for 
orthopedic evaluation. Medical care, 28, 632-4 2. 
Lin, L.1.-K. (1989) A Concordance Correlation Coefficient to Evaluate Reproducibility. Biometrics, 
45, 255. 
Lindwall K, Colstrup L, Wolter IM, et al. Compliance with treatment and understanding of own 
disease in patients with severe and moderate haemophilia. Haemophilia 2006;12:47-51. 
von Mackensen, S., Czepa, D., Herbsleb, M. & Hilberg, T. (2009) Development and validation 
of a new questionnaire for the assessment of subjective physical performance in adult patients 
with haemophilia -the HEP-Test-a. Haemophilia. 170-178. 
Mair FS, May CR. Thinking about the burden of treatment. BMJ. 2014;349:g6680. 
National Institutes of Health (NIH): National Heart, Lung, and Blood Institute. What Is 
Hemophilia? Accessed April 22, 2014; https://www.nhlbi.nih.gov/health/health- 
topics/topics/hemophilia/. 
Nunnally, J. (1978) Assessment of reliability. In Psychometric Theory, Nunnally J & 
Bernstein IH (eds) pp 225-55. MacGraw-Hill Series. 
Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of 
current prophylactic regimens. Blood 2015;125:2038-44. 
Open Science Collaboration, A. (2015) Estimating the reproducibility of psychological science. 
Science, 349, aac471 6- aac4716. 
Shrout, P.E. & Fleiss, J.l. Intraclass correlations: Uses in assessing rater reliability. 
 
 
22
 
 

 
Stratford, P. (2004) Getting more from the literature: estimating the standard error of measurement 
from reliability studies. Physiotherapy Canada. 
Stratford, P.W., Kennedy, D.M., Woodhouse, L.J. & Spadoni, G.F. (2007) Measurement 
properties of the WOMAC LK 3.1 pain scale. Osteoarthritis and Cartilage, 15, 266-272. 
Streiner, D.L., Norman, G.R. & Cairney, J. (2014)Health Measurement Scales: A Practical 
Guide to Their Development and Use Oxford University Press. 
Teal S, Brohan E, Hetteman Y, et al. Development and psychometric evaluation of a novel tool 
for assessing patient perception and preference for haemophilia tretmet (HaemoPREF). 
Haemophilia 2014;20:666-73. 
Theiler, R., Spielberger, J., Bischoff, H.A., Bellamy, N., Huber, J. & Kroesen, S. (2002) Clinical 
evaluation of the WOMAC 3.0 OA index in numeric rating scale format using a computerized 
touch screen version. Osteoarthritis and Cartilage, 10, 479-481. 
Whitehouse, S.L., Lingard, E.A., Katz, J.N. & Learmonth, I.D. (2003) Development and testing of a 
reduced WOMAC function scale. The Journal of bone and joint surgery. 
British volume, 85, 706-711. 
World Federation of Hemophilia report on the annual global survey 2013. Accessed 22 June 
2015. http://www1.wfh.org/publications/files/pdf-1591.pdfFDA (2009) Guidance for Industry Use 
in Medical Product Development to Support Labeling Claims Guidance for Industry. , 1-39. 
Yang, K.G.A., Raijmakers, N.J.H., Verbout, A.J., Dhert, W.J.A. & Saris, D.B.F. (2007) 
Validation of the short-form WOMAC function scale for the evaluation of osteoarthritis of the 
knee. The Journal of bone and joint surgery. British volume, 89, 50-56. 
 
 
 

 
Appendix 1 
Study Investigators 
 
• 
List of responsible parties 
 
Mark Skinner JD, Principal Investigator, Institute for Policy Advancement Ltd. (US) 
Alfonso Iorio MD Ph.D. FRCPC, McMaster University, Department of Clinical Epidemiology and 
Biostatistics (Canada) 
Randall Curtis MBA, Factor VIII Computing (US) Neil Frick 
MS, National Hemophilia Foundation (US) 
Michael Nichol Ph.D. University of Southern California, School of Policy and Planning Development 
(US) 
Declan Noone, Irish Hemophilia Society (Ireland) Brian 
O'Mahony, Irish Hemophilia Society (Ireland) David Page, 
Canadian Hemophilia Society (Canada) 
Jeff Stonebraker Ph.D., North Carolina State University Poole College of Management (US) 
 
24