TREATMENT PATTERNS AND OUTCOMES IN PATIENTS TREATED WITH BENEFIX OR REFACTO/REFACTO AF - A SWEDISH COHORT STUDY
Conditions: Hemophilia A, Hemophilia B
Sponsor: Pfizer

Hemophilia Treatment Patterns and Outcomes in Sweden 
B1821054 NON-INTERVENTIONAL STUDY PROTOCOL 
Final, 16 June 2015  
 
NON-INTERVENTIONAL STUDY (NIS) PROTOCOL 
Study information 
Title 
Treatment patterns and outcomes in patients 
treated with BeneFIX or ReFacto/ReFacto 
AF – A Swedish cohort study 
Protocol number 
B1821054 
Protocol version identifier 
1 
Date of last version of protocol 
16 June 2015 
Active substance 
B02BD09 - nonacog alfa 
B02BD02 - moroctocog alfa 
 
 
Medicinal product 
BeneFIX, ReFacto/ReFacto AF 
Research question and objectives 
The objective of this study is to describe 
demographic and clinical characteristics, 
treatment patterns and outcomes, as well as 
the related treatment costs in the populations 
of hemophilia patients treated with BeneFIX 
and ReFacto/ReFacto AF at the Malmö 
Hemophilia Center. The analyses will be 
carried out for the total populations and for 
subgroups (e.g. level of severity). 
Author 
, PhD 
Health Economics Manager 
Medical GIP and Health & Value, Pfizer AB 
Vetenskapsvägen 10 191 90 Sollentuna, 
Sweden 
Tel: 
 
Email: 
 
 
 
 
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TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS ................................................................................................3 
2. RESPONSIBLE PARTIES ....................................................................................................4 
3. AMENDMENTS AND UPDATES .......................................................................................5 
4. MILESTONES .......................................................................................................................6 
5. RATIONALE AND BACKGROUND ..................................................................................6 
6. RESEARCH QUESTION AND OBJECTIVES ...................................................................8 
7. RESEARCH METHODS ......................................................................................................9 
7.1. Study design ..............................................................................................................9 
7.2. Setting ........................................................................................................................9 
7.3. Exclusion criteria .....................................................................................................10 
7.4. Variables ..................................................................................................................10 
7.5. Data sources ............................................................................................................12 
7.6. Study size ................................................................................................................12 
7.7. Data management ....................................................................................................12 
7.8. Data analysis ...........................................................................................................13 
7.9. Quality control .........................................................................................................13 
7.10. Limitations of the research methods .....................................................................14 
7.11. Other aspects .........................................................................................................14 
8. PROTECTION OF HUMAN SUBJECTS ..........................................................................14 
8.1. Patient Information and Consent .............................................................................14 
8.2. Patient withdrawal ...................................................................................................14 
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............14 
8.4. Ethical Conduct of the Study ..................................................................................15 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................15 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........15 
11. COMMUNICATION OF ISSUES ....................................................................................17 
12. REFERENCES ..................................................................................................................17 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................18 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................18 
 
 
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1. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ICD-10  
International Statistical Classification of Diseases 
and Related Health Problems - Tenth Revision 
IEC 
Independent Ethics Committee 
IHE 
Swedish Institute for Health Economics 
IRB 
Institutional Review Board 
NBHW 
National Board of Health and Welfare 
MHC 
Malmö Hemophilia Center 
MHR 
Malmö Hemophilia Registry 
NIS 
Non-Interventional Study 
PIN 
Personal Identification Number 
SAP 
Statistical Analysis Plan 
SUH 
Skåne University Hospital 
 
 
 
 
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2. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
Name, degree(s) 
Title 
Affiliation 
Address 
, 
PhD 
Health Economics 
Manager 
Medical GIP and 
Health & Value, 
Pfizer AB 
Vetenskapsvägen10, 
S-191 90 Sollentuna, 
Sweden 
 
 
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3.  AMENDMENTS AND UPDATES 
None 
 
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4. MILESTONES 
 
Milestone 
Planned date 
Start of data collection  
01 August 2015 
End of data collection 
31 September2015 
Final study report 
31 November 2015 
Publication submitted 
31 December 2015 
 
5. RATIONALE AND BACKGROUND 
In Sweden nearly 950 people suffer from bleeding disorders. Of these individuals, about 900 
are diagnosed with hemophilia A (insufficient production of coagulation factor VIII) and B 
(insufficient production of coagulation factor IX). The distribution of patients with 
hemophilia A and B is about 80 percent and 20 percent respectively. About 50 people are 
diagnosed with von Willebrand disease [1]. All these patients lack sufficient levels of a 
protein in the blood that impacts the coagulation process. As a result the patients have a 
higher risk of having a bleed as well as suffer from prolonged bleeding. Bleeding can result 
in severe complications, especially in joints, and could result in permanent damage such as 
pain and disability [2]. 
Patients diagnosed with coagulation disorders receive intravenous replacement treatment of 
the missing coagulation factor. Replacement treatment can be given prophylactically, i.e., 
regularly to reduce the insufficiency to prevent bleeding to occur. It can also be given when a 
bleed occurs with the aim to stop the bleed and/or to stop it from becoming more severe, i.e., 
on demand treatment. The type of replacement treatment may depend on the severity of the 
disease [2]. 
At the Malmö Hemophilia Center (MHC) in Sweden patients diagnosed with bleeding 
disorders have been treated prophylactically since 1958. The treatment has intensified over 
time and today patients at the MHC, as well as Swedish patients in general, are treated from 
 
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the age of 1-3 years [2]. Injections with replacement treatment for hemophilia A is generally 
given three to four times a week and for hemophilia B twice a week, when the disease is 
severe.  The patients that belong to the MHC are well monitored - their treatments and 
outcomes have been registered in the Malmö Hemophilia Register (MHR) since 1977. The 
MHR therefore represents the best available source of information on treatments and 
outcomes of hemophilia in Sweden.  
The first type of treatment available for Hemophilia A and B had a low percentage of 
coagulation factors and blood borne viruses such as Hepatitis C and HIV could be transferred 
to the patient. In the 1990’s products that were produced using gene technology, recombinant 
products, with no risk of blood borne viruses, came to the market. Today several such 
products, among them ReFacto that was introduced in 1999 (ReFacto AF in 2009), exist for 
treatment of hemophilia A and most patients are treated with recombinant products [2, 3]. 
For treatment of hemophilia B four different replacement treatments exist and one of them 
(BeneFIX) is produced using gene technology [4]. In the US products with extended half-
life, that make less frequent dosing possible, are available. These products are expected to be 
available in the European market in the end of 2015/early 2016.  
The aim of this study is to analyze the real world use of BeneFIX and ReFacto/ReFacto AF 
in hemophilia patients in Sweden. Sweden has a long tradition of population-based research 
within many therapeutic areas. Information in different registers can be record-linked by 
using the Swedish Personal Identification Number (PIN) that is unique to each Swedish 
citizen. The information available in the MHR linked together with information on 
treatments prescribed and picked up at the pharmacy, available in the Swedish prescription 
register, (held by the National Board of Health and Welfare, NBHW) provide a unique 
opportunity to provide in depth knowledge on actual treatment patterns and outcomes for 
patients diagnosed with hemophilia. 
To our knowledge, no study to date has addressed in detail treatment outcomes, prescription 
patterns, actual treatment patterns, and the associated costs in a cohort of patients with 
coagulation disorders that are treated with BeneFIX or ReFacto/ReFacto AF. Previous 
 
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research that has looked at treatment of hemophilia has e.g. focused on differences between 
the treatment regimens and the associated outcomes, see e.g. Berntorp et al (2012) for a 
review of such articles [5]. Recent research based on Swedish data investigates the long-term 
outcomes in hemophilia patients [6]. Previous research has also focused on real world 
treatment and outcomes in patients with inhibitors (see e.g. Osooli M et al (2015) for a 
systematic review of reasons for inhibitors and on what registries around the world have 
contributed to the learnings about inhibitors) [7-9].  Previous research has also focused on the 
HRQoL of hemophilia patients) [10].   
6. RESEARCH QUESTION AND OBJECTIVES 
This study is explorative, i.e., not hypothesis driven. The overall aim of the study is to describe 
demographic and clinical characteristics, treatment patterns and outcomes, as well as the 
related direct treatment costs in the populations of hemophilia patients treated with BeneFIX 
and ReFacto/ReFacto AF, and in subgroups (e.g. level of severity) at the MHC in Sweden. 
In more detail the primary objectives are:  
• To describe basic demographic and clinical characteristics 
 
• To describe prescription patterns, actual treatment patterns, and the relative dose 
intensity 
 
• To describe treatment outcomes such as bleed and joint damage 
 
• To study the relationship between bleed and actual treatment patterns 
 
• To describe the use of replacement treatment administered in hospital in connection 
with invasive procedures 
 
 
The secondary objectives are: 
 
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• To describe the costs associated with the prescription and actual treatment patterns 
 
• To describe the costs associated with replacement treatment administered in 
hospitals 
 
Patients that develop inhibitory antibodies will be included but analyzed separately. 
7. RESEARCH METHODS  
Methodology for the statistical analyses will be detailed in a statistical analysis plan (SAP).  
7.1. Study design  
The study will be carried out as a retrospective population-based register study. Detailed data 
for each patient diagnosed with hemophilia treated at the Skåne Univeristy Hospital (SUH) is 
collected in the MHR. The hemophilia patients treated at the SUH represent approximately 
40 percent of the Swedish hemophilia population. The information in the MHR will be 
complemented with information from medical records. Information on drugs will be obtained 
from the Prescribed Drug Registry held by the NBHW. The information from the different 
sources will be record-linked at the MHC  using the Swedish PINs that are unique to each 
Swedish citizen  
 
The main strength of this study is that we are able to analyze the questions described in 
section 6. in a population-based setting.  
7.2. Setting 
The study population will consist of all patients diagnosed with hemophilia 
(D66.9 (hemophilia A) D67.9 (hemophilia B) in International Statistical Classification of 
Diseases and Related Health Problems (ICD-10) that have been registered in the MHR since 
1977 and that have had at least one registered prescription of BeneFIX or ReFacto/ReFacto 
AF in the MHR since market authorization of the respective product (Benefix August 27 
1997, ReFacto April 13 1999, ReFacto AF July 1 2009). Diseased individuals are included. 
 
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Information on drugs picked up at the pharmacy is available in the Prescribed Drug Register 
in from2005.  
 
7.3. Exclusion criteria 
There are no exclusion criteria for this study. 
 
7.4. Variables 
 
Background information 
Variable 
Data source(s) 
Description 
Year of birth 
Malmö Hemophilia Register 
 
Year of diagnosis  
Malmö Hemophilia Register 
 
Year of death 
Malmö Hemophilia Register 
 
Age at treatment start  
Malmö Hemophilia Register 
In months 
Sex 
Malmö Hemophilia Register 
1 = man, 2 = woman 
Inhibitor status  
Malmö Hemophilia Register 
Current, ever, never 
Disease severity 
Malmö Hemophilia Register 
Mild, moderate, severe 
Type of bleeding disorder  
Malmö Hemophilia Register 
ICD-10 codes 
Hepatitis C antibody infected 
Malmö Hemophilia Register 
1 = yes, 2 = no 
HIV positive 
Malmö Hemophilia Register 
1 = yes, 2 = no 
Yearly information 
Variable 
Data source(s) 
Description 
Prophylactic treatment 
Malmö Hemophilia Register 
1 = yes, 2 = no 
Body weight  
Malmö Hemophilia Register 
In kilogram at yearly evaluation 
Traumatic Bleed joint 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
 
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Spontaneous bleed joint 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
Traumatic bleed soft tissue 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
Spontaneous bleed soft tissue 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
Intracranial bleed 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
Gastrointestinal bleed 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
Urinary tract bleed 
Malmö Hemophilia Register/Clinical 
records 
Number of bleeds at yearly 
evaluation 
Joint score Gilbert (World 
Federation of Hemophilia 
Physical Examination Score) 
Malmö Hemophilia Register 
Available until 2008/09 
Joint score HJHS 
Malmö Hemophilia Register 
Hemophilia Joint Health Score 
(HJHS)(0-143) (Available from 
2008/09) 
Surgery in joint for 
hemophilia related problems 
Clinical records 
For each surgery information on 
year of surgery and surgery type, 
treatment type and number of 
units 
 
Information on drug prescription 
 
Prescribed dose per infusion 
Malmö Hemophilia Register 
IU,U,µg 
Prescribed dose per kilogram 
Malmö Hemophilia Register 
IU,U,µg 
Prescribed frequency of 
infusion 
Malmö Hemophilia Register 
The weekly number of infusions, 
range from when needed to daily 
Annual consumption of factor 
concentrate 
Malmö Hemophilia Register 
Patient reported consumption 
during calender year 
Information related to each drug expedition 
Variable 
Data source(s) 
Description 
Product prescribed 
The Prescribed Drug Register 
ATC codes 
Prescription date 
The Prescribed Drug Register 
Year month day 
 
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Expedition date 
The Prescribed Drug Register 
Year month day 
Dosage text 
The Prescribed Drug Register 
 
Product identification number  
or package size (Number of 
IU) 
The Prescribed Drug Register 
 
Number of expedited units 
The Prescribed Drug Register 
 
Apris (AIP) 
The Prescribed Drug Register 
 
Ppris (AUP) 
The Prescribed Drug Register 
 
 
 
7.5. Data sources  
Individual data will be extracted from the MHR and supplemented with information on 
surgery and/or bleed episodes from medical records when deemed necessary. Information on 
drugs prescribed and picked up from the pharmacy come from the prescribed drug register at 
the NBHW. The information from the different sources will be record-linked at the MHC by 
using the Swedish PINs that are unique to each Swedish citizen. 
7.6. Study size 
The register that will be used for this study contains information on all Swedish patients 
diagnosed with hemophilia that are treated at the MHC since 1977. The MHC is one of three 
hemophilia centers in Sweden and is responsible for treating about 40 percent of the Swedish 
hemophilia population. The approximate number of patients in the register that are relevant 
for this study amount to about 40 patients for BeneFIX and 20 patients for ReFacto/ReFacto 
AF .  
7.7. Data management  
Data from the MHR and from the NBHW will be record linked and all PIN will be replaced 
by patient study numbers, before they are sent to the vendor, the Swedish Institute for Health 
Economics (IHE). Data management at IHE will include quality and consistency checks. All 
corrections and editing will be tracked for transparency. All data storage and analyses will be 
carried out in statistical software Stata 13.0 or later versions.  
 
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7.8. Data analysis  
All data will be displayed using standard statistical methods. Outcomes will be measured 
using a lifetime perspective while treatment patterns and associated costs will be analyzed 
using shorter time periods. Descriptive statistics will be carried out using frequency and 
percentage for categorical variables and mean, standard deviation, median, min and max for 
continuous variables. 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a SAP, which will be dated, filed and maintained by the sponsor. The SAP 
may modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment. 
7.9. Quality control 
The information in the MHR is of highest quality. The coverage in the register is 100 percent 
for the patients that are diagnosed with hemophilia and treated at the MHC. Quality control 
in the MHR is rigorous. Each data point is checked to ensure the high quality.  
Information for the selected patients in the register will be complemented by information 
from medical records when deemed necessary. This is done by the MHC. Quality control in 
the process is rigorous. Each data entry is checked to ensure the high quality.  
The information from the MHR will further be record-linked with information on relevant 
drugs prescribed and picked up at a Swedish pharmacy. Prescription records and information 
on what prescriptions that were actually picked up at the pharmacy are available in the 
prescribed drug register at the NBHW since 2005. The only exception is when a patient must 
be given emergency treatment at another hospital than SUS. The linking of data will be 
carried out at the MHC. Data will be treated with privacy and according to the Swedish 
Personal data act.  
Data management carried out by the vendor will be tracked so that data editing and other data 
corrections in the preparation of the analysis data sets will be transparent. 
 
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7.10. Limitations of the research methods 
The results from this population-based, retrospective cohort study will not necessarily be 
representative for other patient cohorts. Furthermore, the interpretation of results may be 
hampered by the small number of events available.  
Some information in the register is self-reported e.g. bleeding, this may lead to 
underreporting. Information on prophylaxis that is given in the case of emergency at another 
hospital than SUS is not included in the data. This means that the total cost of prophylaxis is 
potentially underestimated. However, the risk of underestimation is judged to be very small.  
7.11. Other aspects 
Not applicable 
8. PROTECTION OF HUMAN SUBJECTS 
8.1. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. In case of data transfer, Pfizer will ensure that high standards of 
confidentiality and protection of personal data are maintained.  
Data will be analyzed and presented at group level in reports and publications. Informed 
consent is not required due to the retrospective design of the study. The study will be 
advertised and patients included in the MHR will have an opt-out possibility carried out by 
the MHC. Data is anonymized in the file that will be used to carry out the analyses.  
8.2. Patient withdrawal 
Not applicable 
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and opt-out option for the study participants and other relevant 
documents, (e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All 
correspondence with the IRB/IEC should be retained in the Investigator File.  Copies of 
IRB/IEC approvals should be forwarded to Pfizer.  
 
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This study will be sent for approval to the Research Ethics Committee in Lund, Sweden. 
8.4. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR), International Ethical Guidelines for Epidemiological 
Research issued by the Council for International Organizations of Medical Sciences 
(CIOMS), European Medicines Agency (EMA), European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on Methodological 
Standards in Pharmacoepidemiology, and FDA Guidance for Industry: Good 
Pharmacovigilance and Pharmacoepidemiologic Assessment, FDA Guidance for Industry 
and FDA Staff: Best Practices for Conducting and Reporting of Pharmacoepidemiologic 
Safety Studies Using Electronic Healthcare Data Sets, Guidance for Industry: Patient-
Reported Outcome Measures: Use in Medical Product Development to Support Labeling 
Claims and/or equivalent. 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
This study uses existing health care databases, in which it is generally not possible to link 
(i.e. identify a potential association between) a particular product and medical event for any 
individual. In addition, this study protocol requires human review of patient-level unstructured 
data; unstructured data refer to verbatim medical data, including text-based descriptions and 
visual depictions of medical information, such as medical records, images of physician notes, 
neurological scans, X-rays, or narrative fields in a database.  The reviewer is obligated to 
report adverse events (AE) with explicit attribution to any Pfizer drug that appear in the 
reviewed information (defined per the patient population and study period specified in the 
protocol). Explicit attribution is not inferred by a temporal relationship between drug 
 
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administration and an AE, but must be based on a definite statement of causality by a 
healthcare provider linking drug administration to the AE. 
The requirements for reporting safety events on the non-interventional study (NIS) adverse 
event monitoring (AEM) Report Form to Pfizer Safety are as follows: 
• All serious and non-serious AEs with explicit attribution to any Pfizer drug that 
appear in the reviewed information must be recorded on the  chart abstraction form 
and reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form 
• Scenarios involving drug exposure, including exposure during pregnancy, exposure 
during breast feeding, medication error, overdose, misuse, extravasation, lack of 
efficacy and occupational exposure associated with the use of a Pfizer product must 
be reported, within 24 hours of awareness, to Pfizer Safety using the NIS AEM 
Report Form. 
For these safety events with an explicit attribution to or associated with use of, respectively, a 
Pfizer product, the data captured in the medical record will constitute all clinical information 
known regarding these adverse events.  No follow-up on related adverse events will be 
conducted. 
 
All research staff members will complete the Pfizer requirements regarding training on the 
following:   “Your Reporting Responsibilities: Monitoring the Safety, Performance and 
Quality of Pfizer Products (Multiple Languages)” and any relevant Your Reporting 
Responsibilities supplemental training.  This training will be provided to all research staff 
members prior to study start.  All trainings include a “Confirmation of Training Certificate” 
(for signature by the trainee) as a record of completion of the training, which must be kept in 
a retrievable format.  Copies of all signed training certificates must be provided to Pfizer.  
 
 
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10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The results in this study will be reported and discussed in a study report and a manuscript 
that will be sent to a scientific journal for review and publication.  
11. COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer 
product, Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of. 
12. REFERENCES 
 
1. Socialstyrelsen, Blödarsjuka i serien Ovanliga diagnoser; 2011 
2. Svenska riktlinjer för behandling av blödarsjuka, Hemofilicentra i Malmö, Göteborg 
och Stockholm, Förbundet blödarsjuka i Sverige; 2003 
3. European Medicines Agency, European Public Assessment Report for ReFacto 
(Accessed April 27, 2015) 
4. European Medicines Agency, European Public Assessment Report for BeneFIX 
(accessed April 27, 2015) 
5. Berntorp, E., Astermark, J., Baghaei, F., Bergqvist, D., Holmström, M., Ljungberg, 
B., Norlund, A., Palmblad, J., Petrini, P., Stigendal, L. and Säwe, J. (2012), 
Treatment of haemophilia A and B and von Willebrand’s disease: summary and 
conclusions of a systematic review as part of a Swedish health-technology 
assessment. Haemophilia, 18: 158–165. doi: 10.1111/j.1365-2516.2011.02723.x 
6. Lövdahl S, Henriksson KM, Baghaei F, Holmström M, Nilsson JÅ, Berntorp E, 
Astermark J. Incidence, mortality rates and causes of deaths in haemophilia 
patients in Sweden. Haemophilia. 2013 May;19(3):362-9. 
 
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7. Osooli M, Berntorp E (Skåne University Hospital, Lund University, Malmö, Sweden). 
Inhibitors in haemophilia: what have we learned from registries? A systematic review 
(Review). J Intern Med 2015; 277: 1–15. 
8. Chambost, H., Santagostino, E., Laffan, M., Kavakli, K. and The ONE Registry 
Steering Committee on behalf of the investigators (2013), Real-world outcomes with 
recombinant factor VIIa treatment of acute bleeds in haemophilia patients with 
inhibitors: results from the international ONE registry. Haemophilia, 19: 571–577. 
doi: 10.1111/hae.12140 
9. Shapiro, A. D., Neufeld, E. J., Blanchette, V., Salaj, P., Gut, R. Z. and Cooper, D. L. 
(2014), Safety of recombinant activated factor VII (rFVIIa) in patients with 
congenital haemophilia with inhibitors: overall rFVIIa exposure and intervals 
following high (>240 μg kg−1) rFVIIa doses across clinical trials and registries. 
Haemophilia, 20: e23–e31. doi: 10.1111/hae.12329 
10. Lindvall, K., Von Mackensen, S. and Berntorp, E. (2012), Quality of life in adult 
patients with haemophilia – a single centre experience from Sweden. Haemophilia, 
18: 527–531. doi: 10.1111/j.1365-2516.2012.02765.x 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable  
 
  
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 3.0, Effective Date 10-Oct-2014 
 
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