Prospective, Randomized, Crossover Trial Comparing Recombinant Von Willebrand Factor (rVWF) vs. Tranexamic Acid (TA) to Minimize Menorrhagia in Women With Von Willebrand Disease: The VWD Minimize Study
Phase: PHASE3
Conditions: Von Willebrand Diseases
Sponsor: Margaret Ragni

 
i
Prospective, Randomized, Crossover Trial Comparing 
Recombinant von Willebrand Factor (rVWF) vs. 
Tranexamic Acid (TA) to Minimize Menorrhagia in 
Women with von Willebrand Disease: The VWD 
Minimize Study 
 
 
 
 
Short Title:  The VWDMin Trial 
Protocol Number: PRO15070638 
Coordinating Center Protocol Number: PRO17070582 
National Clinical Trial (NCT) Identified Number:  NCT02606045 
Principal Investigator: Margaret V. Ragni, MD, MPH 
 Sponsor: Margaret V. Ragni, MD, MPH 
Funded by: NHLBI 
Version Number:  v5.0 
24 February 2020 
 
 
 
 
 
 
 

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Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Study Design, 
Study 
Population, 
Sections 
2.3.1,  5.2 
Exclusion criteria revised to clarify use of 
hormones (other than progesterone-only), or 
combined oral contraceptives, and 
contraceptive implants in past 3 months. 
While hormonal contraception has been a 
contraindication (when using lysteda, and 
because they increase VWF), progesterone 
alone contraception does not increase 
thrombotic risk nor is it a contraindication 
with Lysteda. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
 
PROTOCOL SUMMARY ............................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................................ 2 
1.2 
Schema .................................................................................................................................................. 3 
1.3 
Schedule of (SoA) ................................................................................................................................ 5 
 
INTRODUCTION ............................................................................................................................................ 5 
2.1 
Study Rationale .................................................................................................................................... 5 
2.2 
Background ........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits .............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 12 
 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 13 
 
STUDY DESIGN ........................................................................................................................................... 13 
4.1 
Overall Design .................................................................................................................................... 13 
4.2 
Scientific Rationale for Study Design .............................................................................................. 14 
4.3 
Justification for Dose ......................................................................................................................... 14 
4.4 
End of Study Definition ...................................................................................................................... 15 
 
STUDY POPULATION ................................................................................................................................. 15 
5.1 
Inclusion Criteria................................................................................................................................. 15 
5.2 
Exclusion Criteria ............................................................................................................................... 15 
5.3 
Screen Failures .................................................................................................................................. 16 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 16 
 
STUDY INTERVENTION ............................................................................................................................. 17 
6.1 
Study Intervention(s) Administration ............................................................................................... 17 
6.1.1 
Study Intervention Description ..................................................................................... 17 
6.1.2 
Dosing and Administration ............................................................................................ 18 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 19 
6.2.1 
Acquisition and accountability ...................................................................................... 19 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 19 
6.2.3 
Product Storage and Stability ....................................................................................... 20 
6.2.4 
Preparation ...................................................................................................................... 20 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................................................... 20 
6.4 
Study Intervention Compliance ........................................................................................................ 21 
6.5 
Concomitant Therapy ........................................................................................................................ 21 
6.5.1 
Rescue Medicine ............................................................................................................ 22 
 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 22 
7.1 
Discontinuation of Study Intervention ............................................................................................. 22 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 23 
7.3 
Lost to Follow-Up ............................................................................................................................... 23 
 
STUDY ASSESSMENTS AND PROCEDURES...................................................................................... 24 
8.1 
Efficacy Assessments ....................................................................................................................... 24 
8.2 
Safety and Other Assessments ....................................................................................................... 25 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 27 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 27 

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8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 27 
8.3.3 
Classification of an Adverse Event .............................................................................. 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 29 
8.3.5 
Adverse Event Reporting .............................................................................................. 29 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 31 
8.3.7 
Reporting Events to Participants ................................................................................. 31 
8.3.8 
Events of Special Interest ............................................................................................. 31 
8.3.9 
Reporting of Pregnancy................................................................................................. 31 
8.4 
Unanticipated Problems .................................................................................................................... 31 
8.4.1 
Definition of Unanticipated Problems (UP)................................................................. 31 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 31 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 32 
 
STATISTICAL CONSIDERATIONS ........................................................................................................... 32 
9.1 
Statistical Hypotheses ....................................................................................................................... 32 
9.2 
Sample Size Determination .............................................................................................................. 33 
9.3 
Populations for Analyses .................................................................................................................. 33 
9.4 
Statistical Analyses ............................................................................................................................ 33 
9.4.1 
General Approach .......................................................................................................... 33 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 34 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 34 
9.4.4 
Safety Analyses .............................................................................................................. 35 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 36 
9.4.6 
Planned Interim Analyses ............................................................................................. 36 
9.4.7 
Sub-Group Analyses ...................................................................................................... 36 
9.4.8 
Tabulation of Individual participant Data .................................................................... 36 
9.4.9 
Exploratory Analyses ..................................................................................................... 36 
 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 37 
10.1 
Regulatory, Ethical, and Study Oversight Consideration............................................................. 37 
10.1.1 
Informed Consent Process ........................................................................................... 37 
10.1.2 
Study Discontinuation and Closure ............................................................................. 38 
10.1.3 
Confidentiality and Privacy ........................................................................................... 39 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 40 
10.1.5 
Key Roles and Study Governance .............................................................................. 40 
10.1.6 
Safety Oversight ............................................................................................................. 40 
10.1.7 
Clinical Monitoring .......................................................................................................... 42 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 45 
10.1.9 
Data Handling and Record Keeping ............................................................................ 46 
10.1.10 
Protocol Deviations ........................................................................................................ 47 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 47 
10.1.12 
Conflict of Interest Policy............................................................................................... 48 
10.2 
Additional Considerations ................................................................................................................. 48 
10.2.1 
Costs and Payments ...................................................................................................... 48 
10.2.2 
Human Subjects ............................................................................................................. 49 
10.2.3 
Qualifications................................................................................................................... 49 
10.3 
Abbreviations ...................................................................................................................................... 51 
10.4 
Protocol Amendment History ........................................................................................................... 52 
11 
REFERENCES .............................................................................................................................................. 53 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
INVESTIGATOR AGREEMENT 
I confirm agreement to conduct the study in compliance with the protocol. 
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise 
the described clinical study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations. Mechanisms are in place to ensure that site staff receives the 
appropriate information throughout the study. 
Investigator Name: 
 
 
Site #: 
 
 
Investigator Signature: 
 
 
Date: 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS  
 
Title: 
 
The Von Willebrand Disease Minimize Menorrhagia (VWDMin) TRIAL 
 
Study Description: 
 
This is a prospective, randomized, crossover multicenter clinical trial 
comparing recombinant von Willebrand factor (rVWF, Vonvendi) and 
tranexamic acid (TA, Lysteda) to reduce menorrhagia in women with von 
Willebrand disease. We hypothesize that intravenous rVWF given on day 1 of 
2 consecutive menstrual cycles is more effective than oral TA three times 
daily on days 1-5 of 2 consecutive menstrual cycles in reducing menstrual 
blood loss and improving quality of life, despite its higher cost and invasive 
route of administration. A total of 60 women (inflated to 66 for anticipated 
10% dropout) with VWD 13-45 years old will be enrolled 24 weeks each in this 
5-year trial.  
Objectives: 
 
The Primary Objective is to determine the efficacy of rVWF vs. TA in reducing 
menorrhagia in women with VWD. 
 
The Secondary Objective is to evaluate safety, tolerability, acceptability of 
rVWF vs. TA in reducing menorrhagia in women with VWD. 
Endpoints: 
The Primary Endpoint is a 40-point reduction in pictorial blood assessment 
chart (PBAC) after 2 cycles.  
The Secondary Endpoints are cycle severity, cycle duration, and quality-of-
life by SF-36, Ruta Menorrhagia Severity Scale, CDC-HRQoL-14, CES-D, and 
satisfaction survey. The cost-effectiveness questionnaire is exploratory.  
Study Population: 
Study subjects will be females age 13-45 years of age with von Willebrand 
disease, defined by VWF:RCo < 0.50 IU/ml (historic or current), previous 
bleeding history, who have menorrhagia and a PBAC >100 in at least one of 
the two preceding menstrual cycles, and cared for at one of the 25 or more 
U.S. centers (HTCs) participating in this trial. Sixty eligible subjects will be 
enrolled (inflated to 66 for anticipated 10% dropout).  
Phase: 
This is a phase III prospective, randomized, crossover trial. 
Description of 
Sites/Facilities 
Enrolling Participants: 
Participating sites include approximately 25 U.S. hemophilia treatment 
centers (HTCs).  
 
Description of Study  
Intervention: 
There are two study interventions: recombinant VWF and tranexamic acid. 
Recombinant von Willebrand factor (rVWF, Vonvendi®) is an FDA-approved 
clotting factor approved for treatment or prevention of bleeds including 
menorrhagia in VWD.  It is an intravenous agent administered in single-use 
vials containing approximately 650-1300 IU mg per vial as a sterile, lyophilized 
powder. The vials are reconstituted with 5-10 ml vial of sterile water for 
injection, USP, which is transferred by two-way needle into the lyophilized 
powder for reconstitution, and the reconstituted vial infused slowly over 5-

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10 minutes, at a dose of 40 mg/kg on the first day of menstrual bleeding in 
two cycles, with a single rescue dose allowed day 2. 
Tranexamic acid (TA, Lysteda®) is an FDA-approved anti-fibrinolytic agent for 
treatment of menorrhagia in bleeding disorders. It is provided as two 650 mg 
tablets for a dose of 1300 mg three times daily for the first 5 days of menstrual 
bleeding in two cycles. 
 
 
       rVWF is recombinant von Willebrand factor concentrate. TA is tranexamic acid; tid is three times 
daily. 
Study Duration: 
This is a 24-week outpatient trial in which all subjects will be randomized to 
one of two treatment arms and followed for up to 24 weeks. Data analyses 
will be completed by 60 months from when the study opens to enrollment.  
Participant Duration: 
The total time for each subject to complete all study visits is 6 months.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 
SCHEMA 
 
Visit 1  
Group 
Cycles 1, 2 
Cycles 3, 4 
Group I 
Arm A: rVWF 40 IU/kg day 1 
Arm B: TA 1300 mg po tid days 1-5 
Group II 
Arm B: TA 1300 mg po tid days 1-5 
Arm A: rVWF 40 IU/kg day 1 
Screening: Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history; physical exam; baseline labs, including hemoglobin, 
hematocrit, platelets, Fe, TIBC, ferritin, TSH, VWF assays (VWF:RCoF, VWF;Ag, FVIII, 
multimers), genotype), urine pregnancy test; PBAC score for the previous 2 cycles; and 
quality-of-life questionnaires, SF-36, Ruta, CDC HR-QoL-14, and CES-D. 

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Week 0-4 
 
 
 
 
Visit 2 
Week 5-8 
 
 
 
 
 
Cycle 1 
Week 9-12  
Cycle 2 
Week 13-16 
 
 
Visit 3 
Week 17  
 
 
 
 
Cycle 3 
Week 17-20 
Cycle 4 
Week 21-24 
 
 
 
Visit 4 
Week 24 
 
 
 
Subjects will perform home pregnancy testing on day 1 of Cycle 3 and Cycle 4, and if 
negative, take initial study intervention on day 1 or days 1-5 of bleeding in the next two 
menstrual cycles, Cycle 3 and Cycle 4, for which they will keep a diary and record PBAC. 
After Cycle 2, but before Cycle 3, subjects will return to clinic for Visit 3, during which 
diaries will be reviewed, and quality-of-life (SF-36, Ruta, HR-Qol-14, CES-D), Satisfaction 
Survey, and Cost-Effectiveness questionnaires will be completed. Subjects in Group 1 will 
cross-over to Arm B, the alternative treatment, and in Group 2 to Arm A. 
 Final Assessments 
After Cycle 4, subjects will return to 
clinic for Visit 4, for history, vital 
signs, QoL, Satisfaction, and Cost-
Effectiveness questionnaires, and 
AE assessment. 
Group 2: Arm B, then Arm A 
 N = 30 subjects 
Group 1 (Arm A, then Arm B) 
N = 30 subjects 
Subjects will perform home pregnancy testing on day 1 of Cycle 1 and Cycle 2, and if 
negative, take initial study intervention on day 1 or days 1-5 of bleeding in the next two 
menstrual cycles, Cycle 1 and Cycle 2, for which they will keep a diary and record PBAC. 
 Enroll and Randomize 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
The Schedule of Events is provided below. 
 
     Study Visit 1 is Baseline/Screen; Visit 2 is Pre-Cycle 1; Visit 3 is Pre-Cycle 3; and Visit 4 is Post-Cycle/End. Cycles are consecutive months 
 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Ineffective therapies for menorrhagia is the greatest unmet healthcare need in women with bleeding 
disorders and menorrhagia, and there are few studies to guide future management this is a critical time 
to initiate a clinical trial of agents to treat menorrhagia in women with VWD. Given the high frequency of 
menorrhagia in women with von Willebrand disease (VWD), the associated morbidity including iron 
deficiency anemia with its social, cognitive, and mental consequences, and the lack of safe, effective 
therapies, it is critical to initiate a clinical trial of agents to treat menorrhagia in women with VWD. 
Although intravenous rVWF is more difficult to administer and costs more than oral tranexamic acid, the 
#1 current recommended non-hormonal treatment for menorrhagia, clinical studies of 101 women with 
VWD and menorrhagia indicate VWF, including both plasma-derived VWF and recombinant VWF, is 
effective in safely reducing menorrhagia in 95% or more (10, 11). Studies of TA indicate it reduced 
menorrhagia by 50% in up to 30% of women with bleeding disorders and menorrhagia (27, 41). With the 
prolonged half-life of rVWF, we anticipate that a single day of rVWF given day 1 of menstrual bleeding in 
the menstrual cycle will reduce menorrhagia to a greater degree than TA given on days 1-5 of the 
menstrual cycle. Given the gaps and unmet needs in the current care and management of menorrhagia in 

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women with VWD, it is a critical time to initiate a clinical trial to address the needs and improve the care 
of women with bleeding disorders. We, therefore, propose this Phase III multicenter prospective, 
randomized, crossover arm trial is to compare recombinant von Willebrand factor (rVWF, Vonvendi) to 
tranexamic acid (TA, Lysteda) in reducing the severity of menorrhagia in women with von Willebrand 
disease. The findings of this study will have potential impact on scientific, economic, and clinical aspect of 
care of women with VWD and menorrhagia. The findings will also provide data on new therapies for 
menorrhagia in women with VWD and other bleeding disorders, which, if successful, will improve clinical 
health outcomes and reduce days lost from work, lifestyle disruptions, psychological morbidity, health 
care cost, and poor quality of life. Further, as VWF is a risk factor for cardiovascular disease, determining 
the lowest effective VWF dose, acceptability of this intravenous therapy in women with VWD population 
will be critical in assuring no increase in thrombosis and cardiovascular disease. Finally, the goals of the 
study, i.e. to prevent complications and blood product safety, are consistent with the goals of Healthy 
People 2020 (40). 
2.2 
BACKGROUND  
Von Willebrand disease (VWD) is the most common inherited bleeding disorder resulting from deficient 
or defective von Willebrand factor (VWF), and characterized by mucosal bleeding in the oropharyngeal, 
gastrointestinal, and genitourinary tract (1-3). Among women with VWD, up to 80% have menorrhagia (4, 
5) which leads to significant morbidity, iron deficiency anemia, high health cost, and poor quality of life. 
Yet, the lack of effective therapy for menorrhagia is the greatest unmet healthcare need in women with 
VWD (5, 6). Up to 30% avoid DDAVP, hormones, or the recommended non-hormonal agent, tranexamic 
acid (TA), as they are ineffective or poorly tolerated (7), and few prospective trials are available to guide 
treatment. 
Two recent trials of rVWF have been conducted: first, a phase I study to assess safety and 
pharmacokinetics of rVWF (8) and a Phase III study to assess efficacy in treatment and prevention of 
bleeding in VWD (9).  In the latter, women with VWD and menorrhagia received rVWF which successfully 
reduced their menstrual bleeding. In these trials, rVWF was given by intravenous infusion, and safely and 
effectively reduced bleeding, and was well-tolerated. rVWF is licensed by the U.S. Food and Drug 
Administration (FDA) for the treatment and prevention of bleeding in VWD. In a survey of 16 hemophilia 
treatment centers, VWF concentrate has been used as a third-line treatment for menorrhagia, only after 
first- and second-line treatment failed: in all 13 subjects receiving VWF there was reduction in heavy 
menstrual bleeding (10, 11). In six published studies (9, 12-16), including two prospective trials, two 
retrospective trials, and two observational network studies, a total of 455 VWD subjects were treated 
with plasma-derived (pd) VWF or rVWF concentrate. Of these, one-third or 88 (19.2%) were women with 
type 1, 2, or 3 VWD and menorrhagia treated with pdVWF at a dose of 36-50 IU/kg for 1-6 days of 
menstrual cycle bleeding (10, 11).  In these studies, 95-100% of these women reported reduction in 
menorrhagia, with no reported adverse effects. The purpose of this study is to compare whether rVWF is 
more effective than TA in reducing bleeding in women with menorrhagia. rVWF is invasive, requiring 
intravenous injection and costs more than oral TA: thus, to justify its use, rVWF should be more effective 
than TA alone. The use of rVWF in VWD is approved by the U.S. Food and Drug Administration (FDA) for 

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treatment of bleeding, including menorrhagia, in individuals with VWD. The formulation of tranexamic 
acid (TA, Lysteda®) in this study is in pill form. The pills are taken by mouth, three times daily. This drug 
and dose are currently licensed by the FDA for treatment of menorrhagia. It is critical and timely to address 
the problem of menorrhagia in women with VWD. We have accumulated data in our U34 feasibility study 
that women with VWD and physicians who care for them are willing to use an intravenous VWF to treat 
women with menorrhagia unresponsive to first and second line drugs, e.g. standard hormonal and non-
hormonal therapy. It is critical to assess response of menorrhagia to rVWF vs. TA, as the findings will 
impact clinical management and improve health outcomes for women with VWD. 
Von Willebrand disease (VWD) is the single most common congenital bleeding disorder, occurring in 1-3% 
of the population (1), and is characterized by deficiency or defect in von Willebrand factor (VWF), a 
glycoprotein that promotes platelet adhesion to vessel wall after vessel injury, which is crucial for platelet 
plug formation, or primary hemostasis, and serves as a carrier protein for factor VIII (2). The VWF gene is 
located on the short arm of chromosome 12 and is encoded by an 8.7 kb VWFmRNA expressed by vascular 
endothelial cells and bone marrow megakaryocytes (3). Typical bleeding symptoms include mucosal 
bleeding in the oropharyngeal, gastrointestinal, and genitourinary tract (1-3). Among women with VWD, 
the most common symptom is heavy menstrual bleeding, or menorrhagia, occurring in more as many as 
80% (3-5).   
Menorrhagia is associated with significant morbidity, including iron deficiency anemia up to two-thirds, 
early hysterectomy, and reduced quality of life (4-5, 17-19). Among women with menorrhagia, the 
prevalence of VWD is 5-20%, with overall prevalence of 13% (4-5, 20). These figures may underestimate 
the true prevalence of menorrhagia, as it may not be recognized as symptom of a coagulation disorder or 
not readily diagnosed, as the extragenic influences of blood group, exogenous estrogens, and stress, may 
increase VWF and lead to apparently normal VWF studies (2-3). Menorrhagia is defined as menstrual 
bleeding exceeding 80 cc/month, a level at which progressive iron loss and iron deficiency anemia occur 
(19). The health burden of menorrhagia is high, with excess days lost from work, lifestyle disruptions, 
psychologic morbidity, poor quality of life, and increased health care costs (17-18). It has been estimated 
that 5-10% of those in reproductive age seek medical attention (21), of whom 50% undergo surgical 
procedure (22). Only recently has consideration of underlying disorders of hemostasis been considered 
important in assessment of the woman with menorrhagia (5), and as a result women presenting with 
heavy menstrual bleeding are screened for bleeding disorders and other pathology prior to the procedure 
(23), resulting in a significant reduction from the nearly 50% of women undergoing hysterectomies for 
menorrhagia in the 1990s (17).  
The “gold standard” for measuring menstrual blood loss by alkaline haematin spectrophotometry in 
collected pads and tampons, but as this is impractical, menstrual history is used in general practice (6). 
The volume of menorrhagia can be quantitated, however, by the pictorial blood assessment chart (PBAC) 
(24). The PBAC is a chart which depicts the degree of pads or tampon saturation during a cycle, which 
when summed for weighted scores for light, moderate, or severe saturation, determines a PBAC score for 
each cycle (24). PBAC has shown good correlation with menstrual blood loss (25): a PBAC score of >100 
strong correlates with menstrual blood loss >80 cc, r=0.85 (24), with 86% sensitivity and 89% specificity 

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(24), and, thus, is considered a quantitative marker of menorrhagia (25). PBAC may be used not only as a 
tool to diagnose menorrhagia, but also as a monitor of therapeutic response after intervention (26, 27). 
A logistic regression model demonstrated that > 80 cc menstrual blood loss is predicted by three variables, 
including the presence of clots >1 inch in diameter, low serum ferritin, and hourly pad/tampon change 
(23). Other nonspecific predictors of menorrhagia include i) bleeding severity score (3, 28, 29), ii) presence 
of flooding, iii) cycle duration >7 days, iv) anemia requiring treatment, v) family history of a bleeding 
disorder, and vi) excess bleeding with dental or surgical procedure, miscarriage or delivery (30). The latter 
four predictors, when coupled to PBAC >100, increase the sensitivity of PBAC to 95% (30). Finally, although 
the severity of nonspecific bleeding in VWD is measured by BSS, and BSS correlates with VWF:RCo level 
(3, 28, 29), neither PBAC nor menorrhagia severity appear to correlate with VWF levels (26, 27). 
The lack of effective treatment for menorrhagia is a major unmet health need among women with 
bleeding disorders (5, 6), and as such constitutes a major public health problem (5, 17, 23). While 80% 
respond to DDAVP (desmopressin) (3, 31, 32), the first-line treatment for type 1 VWD, only 31% use it to 
treat menorrhagia (7), as intravenous infusion is inconvenient and the effect is short-lived, with depletion 
of endothelial VWF stores after three days (31). Response rates with intranasal DDAVP (Stimate®) are 
lower (32-35), related to its less potent effect on VWF release (31).  Although hormonal therapy, 
specifically combined oral contraceptives (OC) are effective in 70% (36), their use is limited by headaches 
and hypertension (32, 36), and only 35% of women with bleeding disorders use these OC to treat 
menorrhagia (7). The levonorgestrel intra-uterine system (Mirena), which releases hormone into the 
endometrial cavity where it is absorbed has antifbrinolytic effect, reducing blood loss (37), but its use is 
limited by weight gain and depression in 20% (37). A recent prospective trial demonstrated the 
antifibrinolytic agent, tranexamic acid (Cyclokapron®, TA), was effective in reducing menstrual blood loss 
by PBAC score in up to 50%, although nausea was a common adverse event (27).  TA is now the 
recommended non-hormonal agent of choice for menorrhagia (27, 38). A new recombinant VWF, rVWF 
(Vonvendi), licensed by the U.S. Food and Drug Administration for treatment of bleeding in von Willebrand 
disease, is a pure VWF protein with intact VWF subunits, produced in the absence of ADAMTS-13, the 
VWF cleaving protein, with a high ratio of high molecular weight and ultra large HMW multimers. This 
accounts for its increased potency over plasma-derived VWF (Humate P) (39), which is the current 
standard VWF concentrate. It is manufactured with no animal or human components. In a phase 1 trial 
rVWF was safe and well tolerated in those with type 3 VWD (8). In a recently completed phase 3 VWF 
efficacy and safety trial (9), rVWF was effective in treatment of 192 bleeds in 22 subjects with a response 
of excellent or good in 100%. There was bleed resolution in 81% of bleeds with a single dose, median 40-
50 IU/kg, with the remainder resolving after a 2nd dose. rVWF was well tolerated with no thrombosis, 
allergic reaction or antibodies to rVWF. 
Given the importance of clinical coagulation evaluation in women with menorrhagia (17, 22, 38), the high 
proportion of women with menorrhagia who have an underlying bleeding disorders (4-7), and the 
identified limitations of current therapies for women with bleeding disorders who have menorrhagia, 
there is consensus that better treatment approaches are needed to improve health outcomes and quality 
of life for women with VWD (3, 5, 38). As ineffective treatment remains the greatest unmet healthcare 
need among women with bleeding disorders (5, 38), which affects quality of care and cost of care, it is a 

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critical time to initiate a study to compare safety and efficacy of rVWF (8, 9) vs. TA (27), the current non-
hormonal agent of choice for menorrhagia in women with VWD and menorrhagia. This is consistent with 
the Healthy People 2020 goal of promoting healthy outcomes, reducing morbidity, and improving quality 
of life, with safe and effective therapies for those affected by bleeding disorders (40). The purpose of the 
proposed Phase III trial will be to compare rVWF vs. TA to reduce menorrhagia in women with VWD. This 
trial will be an outpatient 24-week study conducted in 60 subjects (inflated to 66 for anticipated 10% 
dropout) from approximately 25 HTCs (2-5 subjects locally). IRB protocols will be prepared and submitted 
at each of the study sites. Sites will receive study forms and assessment tools to complete and upload into 
a web-based data base maintained by the University of Pittsburgh Center for Research in Healthcare Data 
Center (CRHC DC). For this trial, the Center for Clinical Trials and Data Coordination (CCDC), which is part 
of the CRHC DC, will serve as the Data Coordinating Center (DCC). A manual of operations will provide 
standardized operating procedures, including enrollment, randomization, data forms, data and specimen 
collection, shipping, and data and safety monitoring reports. Pictorial bleeding assessment charts (PBAC) 
will be completed by study subjects (primary endpoint) and patient diaries will establish subject 
acceptance and adherence to the two intervention arms. Other data collected (secondary endpoints) will 
include cycle duration, cycle severity, quality of life questionnaires, a satisfaction survey, and a cost-
effectiveness questionnaire.  
Based on our survey and literature review indicating VWF is safe and effective in reducing VWD-related 
menorrhagia, we hypothesize that intravenous recombinant von Willebrand factor (rVWF) on day 1 of the 
menstrual cycle is more effective than oral tranexamic acid (TA) three time daily on day 1-5 of the 
menstrual cycle, in reducing menstrual blood loss and improving quality of life, despite its higher cost and 
more invasive route of administration. Bleeding severity by PBAC collected by each subject will be the 
primary endpoint.   
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Risk to Subjects  
There are risks associated with the study drug and having blood drawn.  rVWF and TA will be 
administered during four consecutive menstrual cycles on day 1-5 of bleeding. All subjects will be asked 
to report any safety problems or side effects associated with administration of study drugs.  
 
Risk of Blood Drawing  
There may be discomfort with drawing blood, which is common, occurring in up to 25%, or 25 in 100 
people: this may include pain, lightheadedness, fainting, bruising, or bleeding or infection in the tissue 
around the vein.  This may be alleviated or reduced by applying pressure to the blood draw site for 5 
minutes, and assuming a recumbent position, i.e. lying on your back with your head flat and knees bent, 
if lightheaded. 
 

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Risk of Allergic or Anaphylactic Reaction                                                                                                                      
Allergic-type reactions are rarely reported for rVWF, although were more commonly reported at higher 
dose (e.g. 75 IU/kg, or about 2-fold higher than used in this study), and thus, the risk is expected to be 
uncommon, occurring in < 0.001% or less than 1 in 100,000 people. Allergic reactions for TA are 
expected to be rare in this study, occurring in <.001%, or less than 1 in 100,000 people. Allergic reactions 
could include chills, fever, nausea and vomiting, or rarely may include, in decreasing order of severity, 
death, anaphylaxis (life-threatening difficulty breathing), low blood pressure, heart beat irregularity, 
increase in body fluids, paresthesias (numbness or prickling sensation), urticaria (hives), chest tightness, 
rash, pruritus (itching), edema (swelling), fever, and/or chills. Should these symptoms occur, benadryl, a 
medication which reduces inflammation, may be given, with close monitoring of these symptoms. 
Benadryl may cause drowsiness, dizziness or low blood pressure. Subjects will be monitored for these 
symptoms. No one with a history of allergy (hypersensitivity), an allergic reaction or anaphylaxis 
associated with either recombinant von Willebrand factor (rVWF, Vonvendi®) or tranexamic acid (TA, 
Lysteda®) will be enrolled. Subjects will be monitored closely for early symptoms and signs of 
hypersensitivity reactions, including hives, generalized urticaria, angioedema, chest tightness, dyspnea, 
wheezing, faintness, hypotension, tachycardia, and anaphylaxis. Any subject who develops signs or 
symptoms of an allergic type reaction or anaphylaxis during administration of either study drug will 
immediately have that study drug stopped and appropriate medical care initiated.      
Risk of Thromboembolism/ Thrombogenicity                                                                                                 
Although rVWF and TA may increase coagulation factor levels, they are rarely, if ever, associated with the 
development of thromboembolic complications. There is the unlikely possibility, < 0.001%, or less than 1 
per 100,000 people, that either drug could cause a clot in the vein (thrombosis) with swelling or pain; or 
a clot in the lung (pulmonary embolus) with dyspnea or hemoptysis. The use of oral contraceptives with 
TA may increase risk of venous thromboembolism, and thus will not be allowed during study. This risk will 
be very carefully monitored clinically. Should these symptoms occur measures considered standard of 
care would be implemented to prevent clots: these include either compression stockings, which are 
support-like stockings, and/or sequential compression devices (SCDs). SCDs are blanket-like Velcro-
devices which are placed on the legs to promote blood flow and prevent clots from forming in the leg 
veins. Should a clot occur, treatment would primarily consist of stopping the study treatment and/or 
removing the line in which it was given, if that is the source of the clot, as soon as possible. Should a 
bleeding episode occur during the study period, the subject will be treated with DDAVP or other 
hemostatic agent prescribed by her physician.  
 
Risk of Bleeding Events 
Bleeding symptoms may occur in VWD unrelated to this study, usually with trauma, but sometimes 
spontaneously, without cause. Although unlikely, should a subject have any bleeding during the study, 
she may take her usual standard treatment, DDAVP or VWF concentrate, whichever is usually used. 
 
 

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Risk of Pregnancy 
There are potential risks with pregnancy. rVWF has not been studied in pregnant women. Thus, it is 
recommended that pregnancy should be avoided in subjects on this study. Avoiding sexual activity is the 
only certain method to prevent pregnancy: however, if a subject chooses to be sexually active, she must 
agree to use an appropriate double barrier method of birth control, such as female use of a diaphragm, 
intrauterine device (IUD), sponge and spermicide, in addition to the male use of a condom.  Double 
barrier contraception must be used for at least one week prior to the start of the research study and 
continue for at least two weeks following the last study visit. If a subject chooses to be sexually active 
during this study, she must accept the risk that pregnancy could still result, exposing her to potential 
loss of pregnancy as well as other unknown effects on the developing fetus.  
 
Birth Control Statement 
If a subject becomes aware that that she is pregnant or becomes pregnant during the course of this 
research study, she must contact the principal investigator and physician immediately. The effects of 
rVWF on the fetus (unborn child) are not fully known.  It is therefore important that a subject does not 
become pregnant during this research study. Hormones (other than progesterone-only) or a birth control 
implant will not be allowed during this study because of thrombosis risk.   The double barrier 
contraception must be used for at least one week prior to the start of the research study and continue for 
at least two weeks following the last study visit.  
 
Risk of Inadvertent Disclosure 
Study participation and related data will be protected to maintain confidentiality. There is a possibility 
that the subject’s personal information or genetic material could become generally known. This 
information could impact future insurability, employability, or reproduction plans, or have a negative 
impact on family relationships, and/or result in paternity suits or stigmatization. In order to reduce risks 
of disclosure or breach of confidentiality, the research related documents, blood samples and clinical 
information stored in subject research files will be assigned an alphanumeric (letters and numbers) 
identifier (that do not contain personal identifiers). For this study, a linkage key for linking this number 
and the subject’s name will be kept at each site under lock and key by the PI and his/her research staff.  
 
Breach of Confidentiality 
There is also a potential for possible risk of breach of confidentiality of collected information. To 
minimize this risk, study participation and related information will be protected to maintain 
confidentiality. Blood samples and clinical history will be assigned an alphanumeric identifier and the 
key for linking this number with subject identity will be kept at each site under lock and key by the PI 
and his/her research staff.    The de-identified information in this study will be placed into a secure, web-
based data base at University of Pittsburgh Center for Research in Health Care Data Center (CRHC DC). If 
the investigator publishes research information, subject names will not be identified. 
 
 
 

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2.3.2 KNOWN POTENTIAL BENEFITS  
Potential Benefits 
The subjects will be under close supervision during the study period.  After administration of rVWF or TA 
it is anticipated menstrual bleeding frequency will be decreased from the untreated state. For women 
with menorrhagia, it is already established rVWF and TA may reduce menstrual bleeding, but whether 
one agent is more effective or better tolerated than the other is not known.  
 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Every day clinicians encounter women with von Willebrand disease where a decision to treat menorrhagia 
must be made. However, clinicians do not know what to do because 1) randomized trials and 
observational studies have shown that non-hormonal therapies including the anti-fibrinolytic agent TA, 
and the hemostatic agents, VWF concentrate, are effective in reducing menorrhagia, but side effects, pill 
burden, and requirement for intravenous infusion have limited their use; 2) pathophysiological arguments 
can be made for using either of these agents; 3) observational studies indicate that although they are safe 
and reduce blood loss, these agents are in some only somewhat effective and there is concern about 
thrombosis risk when these agents are used in combination with hormonal therapy; and guidelines 
provide conflicting advice. This has led to practice variation and confusion in the clinical community with 
no clear guidance on safe, optimal treatment for menorrhagia. Based on these findings and existing data 
there clearly is equipoise. For all these reasons, a high quality randomized trial to guide treatment is 
urgently needed to answer this clinically relevant question.  It has been already established that rVWF and 
TA each effectively and safely reduce menstrual bleeding, but whether one agent is more effective or 
better tolerated than the other is not known. The known risks of these agents include, rarely, thrombosis 
and allergic reaction. 
The risks/ benefit ratio indicates the value of the information to be gained outweighs the potential risks 
of participation in the trial as 1) risks associated with rVWF and TA are low, importantly thrombosis risk is 
<0.4% with VWF, based on data from the literature; 2) individuals with cardiac disease, hypertension, MI, 
stroke, thrombosis, or seizure are excluded from the trial; and 3) precautions are in place to protect 
against potential risks, e.g. avoiding hormonal therapy or hormonal implants beginning 3 months before 
and during the trial; and avoiding pregnancy by requiring pregnancy tests on day 1 of each cycle before 
study drug can be taken. Thus, the risk/benefit ratio of participating in the trial outweighs the risk of 
gained outweighs the potential risks of participation in the trial. 
 
 
 

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OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
The Primary Objective is to 
determine the efficacy of rVWF 
vs. TA in reducing menorrhagia in 
women with VWD. 
 
The Primary Endpoint is a 40-
point reduction in PBAC after 
two cycles.  
In a trial of TA 40% of women 
had a 50-point reduction in 
PBAC after 2 cycles, from a 
baseline PBAC score >100. As 
rVWF is i.v. and costs more than 
TA, we estimated rVWF would 
need to improve PBAC 40 points 
more than TA to be adopted into 
practice. 
Secondary 
 
 
The Secondary Objective is to 
evaluate safety, tolerability, 
acceptability of rVWF vs. TA in 
reducing menorrhagia in women 
with VWD. 
 
The Secondary Endpoints are 
cycle severity, cycle duration, 
and QoL by SF-36, Ruta 
Menorrhagia Severity Scale, 
CDC-HRQoL-14, CES-D, and 
satisfaction survey. 
Cycle severity and duration add 
descriptive detail to PBAC. 
Quality-of-life measures were 
used in past studies. The 
satisfaction survey assesses 
intravenous rVWF experience. 
Tertiary/Exploratory 
 
 
An Exploratory Objective is to 
determine cost-effectiveness by 
comparing events prevented and 
cost differences after rVWF vs. 
after TA. 
The Exploratory Endpoint is 
cost-effectiveness determined 
by intervention-specific SF-36 
utility values, and by events 
prevented, e.g. days missed at 
work/school, iron infusion, RBC 
transfusion, ED/ hospitalization. 
As rVWF cost is higher than TA, 
intervention and event costs will 
be estimated after each study 
drug, using CMMS and HCUP 
data, but may be underpowered 
by small sample size and short 
follow-up. 
 
 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
• 
Hypothesis. We hypothesize that intravenous rVWF given on day 1 of menses will be superior to 
oral TA given on day 1-5 of menses, during each of two consecutive menstrual cycles, in reducing 
menorrhagia in women with von Willebrand disease.  
• 
 Phase. This is a Phase III trial. 

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• 
Trial Design. This is a Phase III prospective, randomized, crossover trial. 
• 
Methods to minimize bias. Subjects will have access to VNA, clinic, or infusion center if needed 
to infuse rVWF, and a second “rescue” dose of rVWF will be allowed, as per current practice for 
any bleed. There will be no discrimination by race nor ethnicity. If a woman has iron deficiency, 
she will be treated; if she has hypothyroidism, she will be referred for treatment. All study 
supplies, including study drug, diaries, tampons, and pads, will be provided at no cost. 
• 
Dose escalation or dose-ranging. No dose escalation is planned during this trial.  
• 
Number of study groups/arms and study intervention duration. There are two groups to be 
compared, Group 1, who will be randomized to take Arm A first, then Arm B; and Group 2, who 
will be randomized to take Arm B first, then Arm A. The study intervention duration is 2 
consecutive menstrual cycles each for each agent. For rVWF, this will be day 1 of menstrual 
bleeding for 2 consecutive cycles; and for TA this will be day 1-5 of menstrual bleeding for 2 
consecutive cycles. The order is randomized.   
• 
Single site or multi-site.  This is a multi-site trial, with approximately 25 U.S. hemophilia treatment 
centers. 
• 
Study intervention(s). Subjects randomized to Group I will receive Arm A rVWF 40 IU/kg 
intravenously (IV) infusion on day 1 of each of two menstrual cycles, Cycles 1 and 2. They will then 
be crossed over to Arm B, TA 650 mg 2 tablets orally (po) three times daily on days 1-5 of each of 
two menstrual cycles, Cycles 3 and 4. Subjects randomized to Group II will receive Arm B, TA 650 
mg 2 tablets orally (po) three times daily on days 1-5, for each of two menstrual cycles, Cycles 1 
and 2. They will then be crossed over to Arm A, rVWF 40 IU/kg intravenously (IV) infusion on day 
1 on each of two menstrual cycles, Cycles 3 and 4.   
• 
Interim Analysis. No interim analysis is planned. 
• 
Stratification. No stratification is planned.  
• 
Sub-studies. No sub-studies are planned in this protocol. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
As von Willebrand disease is a rare, orphan disease, we determined that a randomized, cross-over trial 
design would feasible for this trial, and would provide adequate statistical power and allow each woman 
to serve as her own control. There was consensus by our Steering Committee that the design was feasible, 
including the dose of 40 IU/kg. A survey of MDs at the approximately 25 participating HTCs indicated 
agreement on our approach to compare rVWF with TA, and with use a “rescue” dose of rVWF on day 2 of 
the cycle, if menorrhagia was unresponsive. A survey of women with VWD indicated the trial design was 
acceptable, including use of an intravenous drug. Finally, the HTC MDs estimated based on their current 
population well known to them, that they would have at least 75 subjects available over the next 4 years 
for enrollment, sufficient to achieve N=66 subjects (N=60 subjects, with up to 10%, N=6, for dropouts) for 
the trial. 
 
4.3 
JUSTIFICATION FOR DOSE 

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Intravenous rVWF is FDA-approved to treat and prevent bleeds in VWD, including menorrhagia. Limited 
data summarized in a recent review (11) indicate the median dose used in women treated with VWF 
(pdVWF, plasma-derived; or rVWF, recombinant VWF) was 43 IU/kg. In consultation with our Steering 
Committee after review of the literature indicating excellent/good efficacy with rVWF for this indication, 
with <0.4% thrombosis risk, there was consensus to study a dose of 40 IU/kg.  TA is specifically approved 
for this indication at a dose of 1300 mg (2 tables each of 650 mg) three times daily for day 1-5 of menstrual 
bleeding. 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the Schedule of Activities.  
 
 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA   
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. 
Females 13-45 years of age. 
2. 
Mild or moderate von Willebrand disease (VWF:RCo <0.50 IU/ml, past bleeding.  
3. 
Menorrhagia and a PBAC >100 in at least one of the last two menstrual cycles. 
4. 
Regular menses, at least every 21-35 days. 
5. 
Willingness to have blood drawn 
6. 
No prior history of an allergic reaction or anaphylaxis to rVWF or TA. 
7. 
Willingness to avoid ASA and nonsteroidal anti-inflammatory agents (NSAIDS) during the study. 
8. 
Willingness to comply with randomization to rVWF or TA study arms. 
9. 
Willingness to keep a personal diary of menorrhagia bleeding frequency duration and severity by 
pictorial blood assessment chart, and any drugs or hemostatic agents taken. 
10. Willingness to make 4 visits, undergo blood sampling for coagulation studies, and accept 
randomization of two therapies for each of four consecutive menstrual cycles, including an end-of-
study visit. 
11. Willingness to use “double-barrier” method of contraception during the study. 
 
5.2 
EXCLUSION CRITERIA 
Unless otherwise specified, subjects will be excluded from study if any exclusion criteria exist: 
1. 
Any bleeding disorder other than von Willebrand disease; or past thrombotic disease 
2. 
Pregnant or lactating, or use of hormones (other than progesterone-only), or combined oral 
contraceptives, and contraceptive implants in past 3 months.  
3. 
Platelet count < 100,000/ul. 
4. 
Use of immunomodulatory or experimental drugs.  

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5. 
Surgery within the past 8 weeks. 
6. 
Concomitant use of antiplatelet drugs, anticoagulants, dextran, aspirin or NSAIDs. 
7. 
Treatment with DDAVP, cryoprecipitate, whole blood, plasma and plasma derivatives containing VWF 
within 5 days of study. 
8. 
Inability to comply with study requirements. 
9. 
Hypothyroidism as defined by elevated TSH. 
10. Iron deficiency as defined by low serum ferritin, unless iron replacement has been initiated. 
11. History of renal disease 
 
 
5.3 
SCREEN FAILURES 
 
Participants who are consented to participate in the clinical trial, who do not meet one or more criteria 
required for participation in the trial during the screening procedures, are considered screen failures.   
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment:  Females with mild or moderate VWD, age 13-45 years, defined by VWF:RCo < 0.50 IU/mL, 
previous bleeding history and menorrhagia defined by PBAC >100 in at least one of two preceding 
menstrual cycles, who fulfill the inclusion and exclusion criteria, and who are cared for at one of the 
approximately 25 HTCs participating in this trial will be eligible for study. Subjects approached for 
participation in this study will have VWD and be contacted during routine clinic visits to determine their 
interest in participating in the study. There will be no cold-calling. The Site PI will determine the patient’s 
interest in study participation, and, if the patient is interested, the study will be discussed in further detail 
and the informed consent reviewed. Subjects will be encouraged to take time to decide on participation, 
and ask questions. If subjects decide to take a consent form home for further viewing, discussion will 
include the purpose, safety issues, and risks and benefits of the study. All questions will be answered prior 
to and obtaining informed consent.  No experimental procedures or interventions will occur until after 
informed consent is obtained. The investigator’s certification statement will be signed at the time consent 
is obtained. If any new information occurs during the conduct of the study, subjects who have been 
consented will be informed and will be re-consented with this information at the next visit. A de-identified 
prescreening/ screening log will be kept, and all reasons for exclusion documented in study source 
documents and screening log. Subjects who read the consent form are free to refuse enrollment, and 
participants will be free to withdraw at any time. If a subject wishes to withdraw, she may do so by 
addressing a letter to the principal investigator. Any data collected prior to the time of withdrawal will 
continue to be used, but no additional information will be collected. Processed blood sample results will 
continue to be used for the research study; however, remaining samples will be destroyed or used as 
indicated by subject’s letter. The reason (e.g. AE, lost to follow-up, etc.) and date of withdrawal for all 
subjects withdrawn from this study will be recorded. Subject information obtained by electronic data 
capture will be stored and managed on the CRHC DC website. The NIH and IRB may inspect the records of 
this study. Every effort will be made to keep the subject’s personal medical data confidential. Subject 
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rVWF or TA. Subjects will sign informed consent. Subject screening and enrollment will be conducted by 
the local Investigator, in communication with the CRHC DC web-based data entry system. Subjects will be 
considered enrolled in the study after all assessments have been completed during the Screening period 
and just prior to Day 1 of study.  No subject may begin treatment prior to enrollment and assignment of 
a unique subject identification number.  Any subject identification numbers that are assigned will not be 
reused even if the subject does not receive treatment.  
Retention: Retention is a critical issue for clinical trials in rare diseases: to mitigate against concern, blood 
draw is limited to the screening visit, and there are only 4 study visits which will be scheduled after 
menstrual cycles at a time convenient for the subject. Study drugs will be provided at no cost, and assessed 
after 2 menstrual cycles each, which has been shown to be as informative as after 6 menstrual cycles (26). 
rVWF may be given by self-infusion, or by HTC nurses who are trusted and have expertise in caring for 
VWD, and VNA will be available for home and weekend infusions.  In addition, screening and managing 
iron deficiency and hypothyroidism will contribute to the health of these women. Finally, subjects will 
receive compensation for participation in this study, to help defray the cost of meals, travel, and time lost 
from work. The trial will enroll 60 women (inflated to 66 for anticipated 10% dropout), 13-45 years of age, 
recruited during HTC clinic from the approximately 25 U.S. participating HTCs, at a rate of 1 or more per 
HTC per year during the trial. There are no non-U.S. sites. There will be no discrimination based on race 
or ethnicity. Children under 13 as most have not reached regular menses and males will be excluded as 
they have no menstrual cycles.  
 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION   
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Drug Information: Recombinant von Willebrand Factor (rVWF). Recombinant rVWF (vonicog alfa, 
Vonvendi) is approved by the FDA for treatment or prevention of bleeds, including menorrhagia, in VWD. 
rVWF is produced by DNA technology. It is synthesized by a genetically engineered Chinese hamster ovary 
(CHO) cell line that co-expresses both VWF and FVIII genes (39). This is the first VWF manufactured and 
formulated in the absence of animal or other human plasma proteins, thus eliminating the theoretical the 
risk of transmissible agents and other blood-borne pathogens.   It has been established that the ultra large 
and high molecular weight multimers (HMWM) of VWF are essential for platelet plug formation (42). 
Unlike plasma-derived (pd) VWF concentrates which lack ULM due to in vivo proteolytic cleavage by the 
plasma VWF-cleaving protein, ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 
1 motif, member 13), rVWF has no exposure to ADAMTS13 during the production process and thus 
contains intact HMWM and ULM (39). The presence of ULM and the higher purity are associated with 
greater specific activity of rVWF, measured by VWF ristocetin cofactor activity (VWF:RCo) relative to VWF 
antigen (VWF:Ag). The pharmacokinetics of rVWF in patients with type 3 VWF were evaluated in a phase 
1 clinical trial, which showed a longer terminal half-life for rVWF compared to pdVWF and stabilization of 
endogenous FVIII:C (8). ULMs present in rVWF underwent rapid proteolysis by endogenous ADAMTS13 
and no thrombotic events were observed. A subsequent phase III trial recently completed (9) 

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demonstrated that rVWF is safe and hemostatically effective in severe type 1, 2, and 3 VWD patients for 
treatment of bleeds, including menorrhagia. There was a total of 192 bleeds in 22 subjects, with 96.9% 
rating bleed control excellent or good, according to a 4-point scale (4=none to 1=excellent). A single 
infusion was effective in 81.8% of bleeds. In addition, rVWF stabilized endogenous FVIII, and rVWF half-
life was 21.9 hours, and factor VIII activity increase rapidly, achieving hemostatic levels within 6 hours of 
dosing. rVWF was well tolerated. There were serious adverse events in two subjects: chest discomfort and 
increased heart rate, not associated with any cardiac symptoms, and there were no thrombotic or severe 
allergic events, or antibodies to VWF or FVIII (9). 
Drug Information: Tranexamic Acid (TA). Tranexamic acid (TA, Lysteda®) is currently approved by the FDA 
for treatment of menorrhagia (43). rVWF is currently approved by the FDA and will be supplied for use in 
this study by Shire Inc. Both drugs will be distributed by the NIH-contracted pharmacy and shipped to 
HTCs participating in this study as randomization is assigned to enrolled subjects. TA is FDA approved and 
has been used for years with a long safety profile in subjects with bleeding disorders. rVWF is approved 
by the FDA for treatment of bleeding, including menorrhagia, in VWD. TA will be provided as two 650 mg 
tablets for a dose of 1300 mg three times daily for the first 5 days of menstrual bleeding.  
Administration of Study Drugs. Once a subject is identified as eligible for the study and assigned the 
unique subject number by the CRHC DC Web-Based Data System, the individual preparing the rVWF and 
TA will first carefully review the accession number on each drug container or vial, for agreement with the 
accession number assigned to each individual study subject. rVWF will be available for intravenous 
administration in single-use vials containing approximately 650 or 1300 IU per vial, as a sterile, lyophilized 
powder. The 650 IU/vial is reconstituted with a 5-ml vial of sterile water for injection, USP; the 1300 IU/vial 
is reconstituted with a 10-ml vial of sterile water for injection. The resulting solutions for the individual 
650 IU/vial and 1300 IU/vial have a pH of 7.3. A two-way needle will allow transfer of the diluent into the 
lyophilized powder for reconstitution and slow infusion over 5-10 minutes. Storage of rVWF post-
reconstitution should be at room temperature not to exceed 25˚C (77˚F) for up to 3 hours. TA will be 
available for oral administration at a dose of two 650 mg tablets per dose.  Details of the storage, lot 
number, stability, production and expiration dates for each drug, rVWF and TA, will be supplied by the 
contracted pharmacy, McKesson.  
Drug Records for Study Drugs. This study site will maintain accurate records, demonstrating dates and 
amount of study treatment received, to whom dispensed (subject-by-subject accounting), and accounts 
of any study treatment accidentally or deliberately destroyed. McKesson will contract and coordinate the 
process of shipping rVWF and TA to each HTC. It is estimated that McKesson will make shipments of rVWF 
and TA to HTCs every 4 weeks. All pill containers and vials, both used and unused, must be saved for study 
treatment accountability. At the end of the study, reconciliation must be made by HTCs between the 
amount of study treatment supplied, and dispensed. Unused study drugs will be destroyed by study sites. 
A written explanation will be provided for any discrepancies. Unused study drug will be destroyed locally 
at the HTCs. There are no site monitoring visits planned at this time. 
6.1.2 DOSING AND ADMINISTRATION 
  

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Route of Administration of Study Drugs. rVWF dosing will be by study subjects (or VNA or HTC nurse) by 
standard intravenous technique, over 5-10 minutes or less, using a 5-10 cc syringe for injection into a vein. 
TA dosing will be by study subjects by oral self-administration. All drugs by study Group and Arm, rVWF 
or TA, will be taken at the same time each day, preferably beginning at 8 am in the morning.  
Dosing of Study Drugs. rVWF will be given at 40 IU/kg by intravenous infusion over 5-10 minutes by 
standard intravenous technique into a vein on day 1 of menstrual bleeding or TA will be given as two 650 
mg tablets (1300 mg) orally three times daily on the first 5 days of menstrual bleeding during each of 2 
consecutive cycles in up to 60 women (inflated to 66 for anticipated 10% dropout). with VWD. All enrolled 
subjects will be randomized to one of two treatment arms and followed for up to 24 weeks. Follow-up 
visits will occur at week 16 (post cycle 2) and 24 (post cycle 4, end-of-study). All study visit timelines will 
add +/- one day to allow for weekends. Subjects randomized to rVWF will be trained in intravenous 
technique by study nurses, or can set up home visiting nurse for home self-injection. For bleeding not 
relieved after one dose, an additional dose may be given on the following day by HTC MD discretion. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
  
Distribution of Study Drugs. For subjects enrolled on study, rVWF and TA will be shipped from the 
contracted pharmacy, McKesson, to participating HTCs. McKesson will prepare study drug for each study 
subject, per randomization code via web-based accession number, package, and ship to HTCs for study 
subjects. HTCs will store study drugs at 2-8˚C until they are given to study subjects during study visits. Any 
subsequent shipments required will be arranged in the same manner by McKesson to the respective study 
sites, utilizing an accession number assigned by the Data Coordinating Center (DCC), to each vial and to 
each subject, according to treatment arm, which will be linked to the randomization code. McKesson will 
ship a 4-month supply of the study drugs, rVWF and TA, overnight with a temperature recording device 
to HTCs. rVWF will be shipped in the configuration of a vial of lyophilized powder and a matching vial of 
diluent; TA will be shipped as oral tablets in screw top bottles. The study drugs will then be packaged by 
McKesson for each study subject per randomization code.  The HTC nurse will inspect each shipment and 
affix a computer-generated label to study drugs per the randomization code. Included in the shipments 
to HTCs will be forms describing the shipment, total number of bottles and/or vials being shipped, and 
the date of shipment. Study subjects will return all unused vials of study treatment to the HTC which will 
be subsequently destroyed per local procedures. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Formulation and Packaging of Study Drugs. rVWF is formulated as a vial of lyophilized powder and a 
matching vial of diluent; the solution should be clear or slightly opalescent in appearance. TA is formulated 
as a white oval-shaped tablet, non-scored, provided in screw top bottles. Study drugs for each cycle will 
be packaged by McKesson for each study subject per randomization code and shipped to HTCs.  The HTC 
nurse will inspect each shipment and affix a computer-generated label to study drugs per the 

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randomization code. A 4-month supply will be shipped together, with clarification based on 
randomization, which drug is taken during Cycle 1 and 2, and which drug is taken during Cycles 3 and 4. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Storage and Stability of Study Drugs. HTCs will be responsible for immediately opening the shipment of 
rVWF and TA, upon receipt and removing temperature recording devices from the shipment.  The 
temperature information will be recorded as requested on the shipping form provided by each 
distribution center. HTCs will also visually inspect the vials to ensure no damage to bottles or vials occurred 
during shipment and physically count the number of bottles and vials received.  This information will be 
recorded on the forms provided in the shipment by the distribution centers. If there are any discrepancies, 
the distribution centers will be notified immediately and further action taken at that time. HTC sites will 
store packaged, labeled study drug (rVWF) at 2-8˚C and room temperature (TA) until distributed to study 
subject at study visits.  rVWF is stable refrigerated at 2°C to 8°C in the original box and must be protected 
from extreme exposure to light: it is stable typically up to 2 years, per the label. Once reconstituted, if not 
used, it may be stored at room temperature not to exceed 25 °C (77 °F) for up to 3 hours. TA is stable at 
room temperature for up to 2 or more years. 
 
6.2.4 PREPARATION 
 
Preparation of Study Drugs. rVWF is a lyophilized powder that must be reconstituted with Sterile Water 
for Injection (diluent), by two-way needle, inverting diluent over the vial of powder. Once transfer is 
complete, the contents of the vial are gently swirled to completely dissolve the powder. It must not be 
shaken. Once completely dissolved, the contents of the vial are drawn up into a syringe, after which it is 
infused intravenously at a rate of up to 4 ml per minute. 
TA requires no preparation.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Randomization of Study Drugs. Following confirmation of the subject’s eligibility along with the subject 
identification number, the study randomization will be assigned in a 1:1 fashion, and an accession number 
linked with the randomization schema in the database and used for all subsequent study drug allocation. 
Randomization could occur within 72 hours of screening. Study drugs rVWF and TA will be prepared and 
shipped by McKesson to participating HTCs. McKesson will prepare study drugs for each subject based on 
randomization assignment, linked through the CRHC DC web-based data system and shipped to 
participating HTCs for each study subject, where study drugs will be stored at 2-8˚C until they are given to 
study subjects. Pending HTC receipt of study drug shipment, the 24-week trial will begin with the first 
menstrual cycle following randomization. If the subject has a bleed requiring hemostatic agent treatment 
after screening or for other reason, which delays the start of study for greater or equal to 6 months, the 
screening tests must be repeated and a re-verification of eligibility must also take place. Subjects will take 
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of the next 4 consecutive menstrual cycles, with the first assigned study drug for the first 2 menstrual 
cycles, Cycles 1 and 2, followed by crossover to the alternative study drug for the next 2 menstrual cycles, 
Cycles 3 and 4. 
 
Minimization of Bias.  Subjects will be enrolled on the trial based on the investigator verification of 
eligibility, unbiased by race or ethnicity, and recognizing that drug and study arm assignment will be 
performed by the DCC randomization schema. See Demographic Chart below. 
 
Blinding. Not applicable. 
 
 
Demographic Chart: Targeted Enrollment for Study 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2  
0 
2  
Not Hispanic or Latino 
58 
0 
58 
Ethnic Category: Total of All Subjects * 
60 
0 
60 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
6 
0 
6 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
9 
0 
9 
White 
45 
0 
45 
Racial Categories: Total of All Subjects * 
60 
0 
60 
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All Subjects.” 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Compliance. Compliance with study drug will be assessed by patient diary and drug log maintained by 
study subjects during trial and reviewed by study nurses after each of 2 menstrual cycles on rVWF and on 
TA, during visits at the HTC, and also by the electronic database will also maintain track of drug adherence, 
including missed doses.  
   
6.5 
CONCOMITANT THERAPY 
 
Concomitant Medications. Medications taken during the trial will be obtained by medical history, 
including any hemostatic therapy and any other bleeds which may occur during the trial. Bleeds at other 
mucosal sites including epistaxis or gastrointestinal bleeding, which may occur but are unexpected in 
those with VWD, will be recorded on the diary and concomitant medication form. For this protocol, a 

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prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. Medications to be reported in the Patient Diary are concomitant 
prescription medications, over-the-counter medications and supplements. 
 
6.5.1 RESCUE MEDICINE 
 
Rescue Dose of Study Drug. As is standard in clinical practice for any bleed, subjects on this trial will be 
allowed to receive a second “rescue” dose of rVWF for menorrhagia on day 2 of either or both of two 
cycles for which they are randomized to rVWF, for inadequately controlled menstrual bleeding.  The 
rescue dose will be given in the same dosage as the rVWF dose given on day 1 of the two cycles for which 
they are randomized to rVWF. They will record this in their patient diary and report it to the study nurse 
during follow-up visits. 
 
 
 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
   
Discontinuation/withdrawal. All subjects who discontinue study drug will remain on study for follow-
up, especially for safety and efficacy study endpoints.  Reasonable efforts will be made to undertake 
protocol-specified procedures to capture adverse events (AE), serious adverse events (SAE), and 
unanticipated problems (UPs). The date and specific underlying reason for each discontinuation or 
withdrawal will be captured by a separate case report form. 
Considerations for Stopping the Trial. It is possible that the test statistic will cross the monitoring 
boundary. Statistical interim monitoring results should be taken as one component to the decision as to 
whether or not to stop a trial. To stop the trial for efficacy, results should be definitive enough to be able 
to change clinical practice. The DSMB will use the monitoring information to determine its 
recommendation to NHLBI. The DSMB can recommend that the trial should continue as proposed, that 
the protocol should be modified based on the results seen in one treatment comparison or in some well-
defined subgroup of patients, or that the trial should be terminated early. The final decision to stop trial 
rests with the NHLBI. If recommendation is to stop the trial, the trial principal investigators shall be 
consulted before a final decision is made. 
We will allow the trial to run to completion if the intervention appears at least as effective as standard 
TA therapy. We propose halting the trial if a safety event reaches any stopping rules: (i) uncontrolled 
menstrual bleeding; (ii) thrombosis; or (iii) or grade 2-5 allergic reactions. Please see section 9.4.4. The 
DSMB will review each event to determine if the trial should be halted.  Statistical interim monitoring 
results should be taken as one component to the decision as to whether or not to stop a trial. To stop 
the trial for efficacy, results should be definitive enough to be able to change clinical practice. The DSMB 
will use the monitoring information to determine its recommendation to NHLBI. The DSMB can 

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recommend that the trial should continue as proposed, that the protocol should be modified based on 
the results seen in one treatment comparison or in some well-defined subgroup of patients, or that the 
trial should be terminated early. The final decision to stop trial rests with the NHLBI. If recommendation 
is to stop the trial, the trial principal investigators shall be consulted before a final decision is made. 
Suspension and Stopping Rules 
According to the protocol Safety Stopping Rules, the trial will be terminated if an event(s) reach any 
stopping rules. A terminated trial means no further subjects are enrolled or treated. If an event(s) trigger 
any suspension rules, the study will put on hold until the DSMC and Medical Monitor evaluate the event 
and make a final recommendation. A suspended trial means no further subjects are enrolled, but 
already enrolled subjects will be treated. In addition, all subjects who develop inhibitors, no matter the 
treatment they receive, will be monitored. 
   
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
   
Discontinuation/ Withdrawal. Study subjects are free to withdraw from participation in the study at any 
time upon request. An investigator may discontinue or withdraw a participant from the study for the 
following reasons: 
• 
Pregnancy 
• 
Significant study drug non-compliance  
• 
If continued participation in the trial, e.g. because of any clinical adverse event, laboratory 
abnormality, or other medical condition or situation would not be in the best interest of the 
subject 
• 
If the subject meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation, e.g. elevated TSH indicating hypothyroidism 
• 
If the subject is unable to receive study drug for the prescribed duration, and/or complete it. 
The date and specific reason for participant discontinuation or withdrawal from the study will be recorded 
on a separate Case Report Form. Subjects who sign the informed consent form and are randomized but 
do not receive the study intervention may be replaced.  Subjects who sign the informed consent form, 
and are randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study may also be replaced.  It is anticipated that up to 10% (6) subjects will 
discontinue or drop out of the trial; thus, 66 subjects will be enrolled to assure 60 subjects complete it. 
7.3 
LOST TO FOLLOW-UP 
 
Lost to Follow-up. Study subjects will be followed for a total of 24 weeks during the trial. Validity of the 
study is at risk when subjects are lost to follow-up, as information for endpoint documentation and 
evaluation is then lost. A study subject will be considered lost to follow-up if she fails to return for a 
scheduled visit and is unable to be contacted by the study site staff.  
    

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The following actions must be taken if a participant fails to return for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 4 weeks 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if she wishes to and/or should continue in the study. 
• 
Before a subject is deemed lost to follow-up, the investigator will make every effort to regain 
contact with the subject, including up to 3 telephone calls and, if necessary, a certified letter to 
the subject’s last known mailing address or local equivalent methods. These contact attempts will 
be documented in the subject’s study file.  
• 
Should the subject continue to be unreachable, she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
 
 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
• 
This section includes a list and description of the efficacy assessments to be conducted on the 
trial. 
• 
PBAC Score. The PBAC will be scored for the 2 previous menstrual cycles and as the primary 
efficacy outcome of the trial for each cycle on the trial. PBAC at screening will be scored by the 
subject to determine eligibility, which per definition of menorrhagia, requires the PBAC score be 
>100 for at least one of two previous menstrual cycles. If the PBAC is not above 100 in past two 
cycles, this constitutes exclusion from participation. PBAC for each cycle, including Cycle 1 and 2 
on study drug (either rVWF or TA) will be compared to PBAC for cycles 3 and 4 on study drug 
(either TA or rVWF).  
• 
Cycle Severity Rating (CS) and Cycle Length (CL). The cycle severity (CS) and cycle length (CL) 
will be rated by numeric scale 0-3, and recorded in diaries. This will rate the severity of each 
cycle by a single score: ratings include: 0=mild bleeding much less than usually experienced; 
1=moderate bleeding less than usually experienced; 2=moderately severe bleeding but not as 
bad as the worst menstrual bleeding experienced; and 3=severe bleeding, as bad as the worst 
menstrual bleeding experienced. Cycle length (CL) will be in days of tampon/pad use on PBAC. 
These measures will provide more subjective ratings than PBAC, and as such, will provide 
distinct data separate from the primary endpoint. 
• 
Quality-of-Life Questionnaires. The impact of the two study interventions on quality of life will 
be determined by SF-36, Ruta Menorrhagia Severity Score, CDC-HRQoL-14, and CES-D, 
measured at baseline, and after the first two cycles (Visit 3), and after the second two cycles 
(Visit 4). The Short-Form-36 (SF-36) is a 36-item general health survey in eight areas of physical 
and mental health (67, 68), which has been validated in women of reproductive age and strongly 
associated with VWD phenotype: lower SF-36 scores correlate with higher bleeding scores (69). 
The Ruta Menorrhagia Severity Scale is a 15-item instrument that measures the physical, 

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psychological and social effects of menorrhagia (70), and is validated for menorrhagia: higher 
scores correlate with reduced PBAC (13). The CDC Health-Related Quality of Life (HRQoL-14) is 
a 14-item instrument that assesses “healthy days” including the number of physically and 
mentally unhealthy days in the past 30 days, and has been standardized for women of 
reproductive age (71). The Center for Epidemiology Studies Depression (CES-D) Scale is a 20-
item screen for depression that identifies depression symptoms over a range of ages and 
demographic groups (72).  It is expected that QoL score by these 4 scales will improve with study 
drugs and correlate with the reduction in menorrhagia by PBAC score. 
• 
Satisfaction Survey.  A Satisfaction Survey will be assessed after two cycles of rVWF in which 
subjects will a) rate treatment with rVWF as compared with their usual treatment of heavy 
menses; b) rate how difficult or problematic the use of rVWF was; and c) indicate if rVWF will be 
considered for use in future menstrual cycles. It is anticipated that if rVWF results in no better 
improvement than TA, satisfaction will be lower, and the use of rVWF may not be justified.  
• 
Cost-Effectiveness Questionnaire. Given rWF burden (IV route, cost), we will collect cost-
effectiveness data (i.e. days lost from work/school, and need for iron infusion, RBC transfusion, 
or ER or hospital care) and compare events prevented and cost savings after 2 cycles on each 
treatment. Intervention and event costs will be estimated using data for Centers for Medicare 
and Medicaid Services (CMMS) and Healthcare Cost Utilization Project (HCUP) (73). The 
effectiveness term in the analyses will be intervention-specific SF-36 QoL utility values (74). Data 
will also be compared by general estimating equations (75), which may be underpowered by the 
small sample size and short trial follow-up (76), and thus, will be an exploratory endpoint. 
Please refer to MOP for detailed description of study procedures. 
   
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
This section includes a list and description of the safety assessments to be conducted on the trial. 
• 
Screening Laboratory Evaluations. Baseline laboratory studies will be drawn at screening, 
including Blood Counts: hemoglobin, platelets; Iron Tests: iron, TIBC, ferritin; Thyroid Test: TSH; 
and Von Willebrand Tests (VWF:RCo (activity), VWF:Ag, VIII:C, multimers, and VWF genotype). 
Before initiating treatment, subjects will be trained by the HTC nurse on 1) reading urine 
pregnancy tests and 2) completion of the pictorial blood assessment chart (PBAC), cycle severity 
rating (CR), and cycle length (CL); and 3) completion of patient diary. The Blood Counts, Iron Tests, 
and Thyroid Test will be performed by Quest laboratories. Any subject who has hypothyroidism, 
defined by an elevated TSH; or who has iron deficiency as defined by low serum ferritin, if 
untreated, are ineligible. If the MD initiates iron therapy in a patient with low serum ferritin, she 
is eligible to participate on the trial. The VWF Assays will be performed at the University of North 
Carolina FOBRL laboratories, Chapel Hill NC, and the VWF genotype will be performed by 
Functional Bioscience, Madison WI. These laboratories are in compliance with and have on record 
updated Clinical Laboratory Improvement Amendments (CLIA) certificates. The Table below lists 
for each of the specific laboratory assays, the estimated volume and type of specimen needed for 

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each test, conditions for specimen preparation, shipping, and the laboratory receiving the sample 
and performing the assay. 
• 
Urine Pregnancy Test. A urine HCG pregnancy test will be performed by each subject at baseline 
and at the onset of menstrual bleeding in each of 4 cycles during the trial. Study drugs may be 
used only after a negative urine pregnancy test. Nurses will train subjects in how to administer 
and read the test. If the test is positive, subjects may not take study drugs, and must notify their 
HTC and physician and nurse immediately. 
• 
Brief Medical History, Vital Signs, and Physical Examination: To establish baseline status, a brief 
medical history, physical exam, and vital signs will be obtained. The medical history will include 
all medical diagnoses, surgeries, current medications, concomitant medications, and any allergies. 
Vital signs will include temperature, pulse, respirations, blood pressure, height, and weight. The 
physical exam will include targeted HEENT, chest, abdomen, extremities, neurologic, and skin 
assessment. Subsequent visits will assess interval change by interim history and vital signs.   
• 
Patient Diary and Drug Log. The Patient Diary will capture information collected by the study 
subject, including the PBAC score, cycle severity (CS), cycle duration (CSL), other bleeds and use 
of “rescue” dose of rVWF. The drug log will keep track of dose and frequency of study drugs taken, 
any missed doses, date and reason for missed doses, and adherence to study drug. 
• 
Assessment of Adverse Events. The provisions for follow-up of ongoing AEs/SAEs will include 
monitoring all subjects for allergic reactions, thrombosis, or uncontrolled bleeding. Any adverse 
events will be monitored by the HTC physician until resolution of each AE or SAE. The degree of 
relatedness to study drugs will be determined, duration of adverse event, any medication given 
to treat the subject, and time to resolution of the event. 
• 
Availability of Lab Results to Subjects. The results of Blood Counts, Iron tests, and Thyroid Tests 
will be made available to study subjects, and will establish eligibility. The results of the VWF assays 
and multimers, and VWF genotype will be used for research purposes only, to compare with PBAC 
scores by study arm. As previously noted, a subject’s medical chart or results of diagnostic tests 
performed as part of individual regular medical care may be used for screening or as a part of data 
collection. Therefore, the Health Insurance Portability and Accountability Act (HIPAA) rules, other 
relevant federal or state laws, and local institutional requirements will be followed, as applicable. 
Information regarding past VWD diagnosis, and PBAC score from past menstrual cycles will be 
reviewed to help determine eligibility. 
Lab Assay 
Tests 
Volume/Type Tube 
Preparation/Shipping/ Laboratory 
Blood Counts 
Hemoglobin, 
platelets 
One 4.0 ml EDTA purple 
top 
No preparation for EDTA tube. Ship ambient by Fed Ex to: Quest 
Diagnostics, 875 Greentree Road, Four Parkway Center, Pittsburgh 
PA, 15220. 
Iron Tests 
Iron, TIBC, ferritin 
One 4.0 ml SST tube 
No preparation for SST tube. Ship ambient by Fed Ex to Quest 
Diagnostics, as above. 
Thyroid Tests 
Thyroid stimulating 
hormone (TSH) 
(part of SST tube above) 
No preparation for SST tube. Ship ambient by Fed Ex to Quest 
Diagnostics, as above. 

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An Adverse event (AE) is defined as an untoward or unfavorable medical occurrence in a human 
participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with a person’s participation in the research, whether or 
not considered related to a person’s participation in the research (21 CFR 312.32 (a))]. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
A Serious Adverse Event (SAE) is defined as an adverse event that meets any of the following criteria: 
• 
results in death; 
• 
is life-threatening i.e. places a subject at immediate risk of death from the event as it occurred; 
• 
requires inpatient hospitalization or prolongation of existing hospitalization;  
 
     The latter is not regarded as an SAE if: 
(i)    The admission results in a hospital stay of less than 12 hours; OR 
(ii)   The admission is pre-planned, i.e. scheduled surgery arranged prior to study; OR 
(iii)  The admission is not associated with an AE (e.g. social hospitalization for respite care) 
 NB: An invasive procedure during any hospitalization may be reported as an SAE 
• 
results in a persistent or significant disability/incapacity; 
• 
results in a congenital anomaly/birth defect; OR 
• 
any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
   
Classification of Adverse Events 
   
VWF Assays 
VWF:RCo, VWF:Ag, 
FVIII:C, multimers 
Three 5.0 ml CITRATE 
blue top tubes 
Spin 15 minutes at 3000 rpm (1300 g), at 4°C. Transfer plasma to 
15 ml conical tube and spin for 7 minutes at 3000 rpm (1300g), at 
4°C or room temperature. Aliquot into 4 x 200 µl cryovials and 
freeze at -70°C to -80°C until shipped overnight, frozen by Fed Ex 
to Dr. Tim Nichols, FOBRL, UNC 125 University Lake road, Chapel 
Hill NC 27516. 
VWF Genotype 
VWF genotype 
One 5.0 ml EDTA purple 
top tube 
Ship ambient by Fed Ex to Mr. Mike Meyer, ITxM Coagulation 
Laboratory, 3636 Boulevard of the Allies, Pittsburgh PA 15213. 
Samples will be batched and sent at end study to Functional 
Bioscience, 505 South Rosa Road, Suite 238, Madison WI  53719.  

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Severity. The severity of the adverse event refers to the intensity of an event and is categorized as: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated, 
Moderate; minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental 
activities of daily living, 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care activities of daily living, 
Life-threatening consequences; urgent intervention indicated, 
Death related to AE. 
 
       As an alternative, standard grading may be used, e.g. CTCAE, grade 1 to grade 5. If used, a   
       “translation” between the CTCAE system and the standard grading above will be provided. 
 
    
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
Relationship. Relatedness refers to the extent to which an adverse event is considered to be related to 
the intervention or study procedures. An adverse event is considered related if there is a reasonable 
possibility that the event may have been caused by the procedure. Note that the term “suspected” is 
also means possibly, probably or definitely related to the intervention or study procedures. The following 
definitions apply to relatedness: 
1. Unrelated 
• 
Adverse event is clearly due to extraneous causes (e.g., underlying disease, 
environment) 
2. Unlikely (adverse event must meet 2 of the following): 
• 
Does not have temporal relationship to intervention 
• 
Could readily have been produced by the participant’s clinical state 
• 
Could have been due to environmental or other interventions 
• 
Does not follow known pattern of response to intervention 
• 
Does not reappear or worsen with reintroduction of intervention 
3. Possible (adverse event must meet 2 of the following): 
• 
Has a reasonable temporal relationship to intervention 
• 
Could not readily have been produced by the participant’s clinical state 
• 
Could not readily have been due to environmental or other interventions 
• 
Follows a known pattern of response to intervention 
4. Probable (adverse event must meet 3 of the following): 
• 
Has a reasonable temporal relationship to intervention 
• 
Could not readily have been produced by the participant’s clinical state or have been due 
to environmental or other interventions 
• 
Follows a known pattern of response to intervention 
• 
Disappears or decreases with reduction in dose or cessation of intervention 

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5. Definite (adverse event must meet all 4 of the following): 
• 
Has a reasonable temporal relationship to intervention 
• 
Could not readily have been produced by the participant’s clinical state or have been due 
to environmental or other interventions 
• 
Follows a known pattern of response to intervention 
• 
Disappears or decreases with reduction in dose or cessation of intervention and 
recurs with re-exposure 
 
 
8.3.3.3 EXPECTEDNESS  
Expectedness. An unexpected event is one that has not been documented previously as an established 
adverse reaction to the study intervention and that is not recognized as part of the natural progression 
of the disease. A particular event may also be considered unexpected if it has a higher severity grade 
than what has been documented or identified previously. 
   Action:  Any action taken while on study drug to resolve the AE is to be documented as follows: 
• 
Drug withdrawn 
• 
Drug interrupted 
• 
Dose not changed 
• 
Dose increased 
• 
Not applicable 
   Outcome:  The outcome of the AE is to be documented as follows: 
• 
Not recovered/resolved 
• 
Recovered/resolved 
• 
Recovered with sequelae 
• 
Recovering/resolving 
• 
Fatal  
• 
Unknown 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Data Collection Procedures for Adverse Events. The clinical site staff will report all SAEs on the trial data 
collection forms. Expected serious adverse events are listed in the manual of operations; these events 
are recorded on the in-hospital and the 30-day follow-up data collection forms. Site personnel are 
required to report and document all unexpected SAEs and UPs to the DCC. The DCC will send 
unexpected SAEs (as reported by the site) to the study Medical Monitor for final assessment of severity, 
relatedness, and expectedness.  
 
8.3.5 ADVERSE EVENT REPORTING  
Reporting Procedures. All reported SAEs and unanticipated problems will be included in systematic 
reporting to the DSMB on a semi-annual basis. This includes adverse events and problems previously 
transmitted through expedited reporting. The following three classes of events will be reported to the 
NHLBI, the DSMB and the local IRB in an expedited manner: 1) Fatal or life threatening unexpected 

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suspected SAE, 2) Non-fatal, non-life threatening unexpected suspected SAE, and 3) Unanticipated 
problem. Fatalities related to blood transfusions must be reported to the FDA within 7 days according to 
guidance: (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ 
Guidances/Blood/ucm074947.htm). If a particular SAE is reported with abnormally high frequency 
during the trial, this will be submitted to the Medical Monitor at NHLBI for review. Site personnel will 
complete and submit an SAE form to the DCC within 24 hours of learning of the event whenever the 
event is both serious and unexpected. In cases where the event is not serious but places the patient at 
greater risk of physical, psychological, economic, or social harm, and is both unexpected and related to 
the study, the sites will notify the DCC within 14 days of learning of the event.  SAE forms will be 
forwarded along with relevant patient history data to the Medical Monitor for review. The study 
Medical Monitor will assess severity, relatedness, and expectedness of the event within 48 hours.    
DCC Reporting for Study Sites. Following the Medical Monitor’s feedback, the DCC will complete an SAE 
report for adverse events categorized as serious, unexpected and related and submit the SAE within 72 
hours of learning of the event to the NHLBI Project Officer and to the DSMB Executive Secretary. The 
DCC will also send a final (or updated) report by 7 days of learning of the event.  A report will also be 
sent for unanticipated problems. The DCC will send the reports to the NHLBI DSMB Executive Secretary 
and the NHLBI Medical Monitor for review. All reporting from the time that the Site learns about the 
event until it is reported to the NHLBI, DSMB, FDA and IRBs will follow the NHLBI DSMB established 
timelines as specified in (https://www.nhlbi.nih.gov/research/funding/human-subjects/adverse-event) 
and shown above.  Upon receipt of an expedited report, the DSMB chair will decide whether the event 
should be discussed at the next scheduled DSMB meeting or discussed as soon as possible at an ad-hoc 
meeting. 
 Reporting of Local IRB Actions. All adverse events experienced by study subjects from the time of 
dosing until 30 days after administration is to be recorded on the CRF, regardless of the severity of the 
event or its relationship to study treatment. The serious AE reporting procedures are based on the 
“Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events” (CTCAE) (49). 
Subjects will report any AE or SAE to the HTC co-investigator or nursing coordinator. All AEs, regardless 
of severity, will be followed up by HTC Investigator until satisfactory resolution. All subjects experiencing 
AEs using investigational product, will be monitored until symptoms subside and any abnormal 
laboratory values have returned to baseline, or until there is a satisfactory explanation for the changes 
observed, or until death, in which case a full pathologist's report will be supplied, if possible. Withdrawal 
from the clinical study and therapeutic measures shall be at the discretion of the investigator. IRB 
actions regarding the trial will be communicated to the NHLBI Project Officer and NHLBI Executive 
Secretary in an expedited fashion. If the IRB or ethics board at any site, CCC or DCC takes action 
regarding the trial (e.g., the IRB places a hold on the trial or suspends the trial), the site will report this to 
the CCC within 24 hours of the action. The Site will submit written documentation from the IRB, an 
explanation of the circumstances, and a plan of action to the CCC within 72 hours. The CCC will promptly 
communicate this information to the DCC and the NHLBI project officer and DSMB Executive Secretary. 
Adverse Event Reporting Period. All randomized patients will be followed for 24 weeks. Reporting of 
AEs will cease at the conclusion of the trial. 
 

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8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
See Table. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Reporting of adverse events to study subjects will follow Informed Consent guidelines, to assure subjects 
are aware of risks and benefits, and any event that might change the balance of risks and benefits. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
  
Not applicable. 
8.3.9 REPORTING OF PREGNANCY  
 
Study subject will perform a urine pregnancy test on the first day of menstrual bleeding for each of 4 
cycles on study. If the test is positive, no study drug may be taken, and the result of the pregnancy test 
must be reported immediately to the physician.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
An Unanticipated Problem (UP) is defined as any incident, experience, or outcome that meets 
all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency, taking protocol research procedures and 
participation population characteristics into consideration. 
• 
Related or possibly related to a person’s participation in the research. 
• 
Places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
   
8.4.2  UNANTICIPATED PROBLEM REPORTING  
See Table. 
TABLE:  NHLBI Serious Adverse Event and Unanticipated Problems Reporting Timelines 
What Event is Reported 
When is Event Reported 
By Whom is 
Event Reported 
To Whom is Event 
Reported 
Fatal or life-threatening unexpected, 
suspected serious adverse reactions 
Within 24 hours of event. 
Investigator 
DCC, Local/Internal IRB  
Within 72 hours of event. 
DCC 
NHLBI, DSMB 
Within 7 calendar days of event 
DCC 
NHLBI, DSMB  
Within 15 calendar days of initial 
receipt of information 
Investigator 
DCC, Local/internal IRBs 

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Non-fatal, non-life-threatening 
unexpected, suspected serious 
adverse reactions 
Sponsor  
FDA, All investigators 
Unanticipated Problem that is 
not an SAE 
Within 14 days of the investigator 
becoming aware of the problem 
Investigator 
DCC, Local/internal IRBs 
NHLBI, DSMB 
All Unanticipated Problems2 
Within 30 days of the IRB’s receipt of the 
report of the UP from the investigator. 
IRB 
OHRP 
Investigator3 
External IRBs 
  1. Designee is appointed by the sponsor; for example, DCC, CRO. 
  2.  Per OHRP guidance: only when a particular AE or series of AEs is determined to meet the criteria for an UP should a report of the AE(s) be     
       submitted to the IRB at each institution under the HHS regulations at 45 CFR part 46.   Typically, such reports to the IRBs are submitted by    
       investigators. 
  3. Investigators should also take into account local IRB guidance if reporting timelines for UPs are shorter than OHRP guidance. 
 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Reporting of unanticipated problems to study subjects will follow Informed Consent guidelines, to assure 
subjects are aware of risks and benefits, and any event that might change the balance of risks and benefits. 
 
 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
There will be a formal Statistical Analysis Plan (SAP), completed prior to database lock and unblinding of 
the study data.  Please refer to the SAP for additional information. 
 
The primary endpoint is the pictorial blood assessment chart (PBAC) score, a validated measure of 
menstrual blood loss. PBAC scores from all four periods of the crossover trial (AABB/BBAA) will be utilized 
in statistical analyses.  The null hypothesis is that there will be no difference in PBAC score improvement 
from baseline between intravenous rVWF and oral TA treatments.  Our alternative hypothesis is that rVWF 
will be superior, producing a greater improvement in PBAC score compared to treatment by oral TA.  
Specifically, we hypothesize that intravenous rVWF will improve PBAC score by at least 40 points more 
than TA.  
   
The secondary endpoints include frequency of menorrhagia unresponsive to study drugs or rescue, by 
Patient Diary, Drug Logs, Cycle Severity Rating (CS), Cycle Length (CL), Quality-of-Life (QoL) forms, 
including SF-36, Ruta, CDC-HRQoL-14, and CES-D; and satisfaction as measured by surveys. Additionally, 
response to treatment will be compared with VWF assays and VWF genotype. Our secondary hypotheses 
will evaluate the safety, tolerability and acceptability of rVWF versus TA as measured by outcomes such 
as frequency of menorrhagia unresponsive to study drugs or rescue, CS, CL, QoL questionnaires and 
satisfaction surveys. We hypothesize that rVWF will be as safe, tolerable and acceptable as TA in the 

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reduction of menorrhagia.  Additionally, we hypothesize that VWF assays and VWF genotype will 
significantly predict response to study treatment.   
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Sample Size and Statistical Power: We propose a phase III multicenter, prospective, randomized 
crossover trial to compare IV rVWF vs. po TA in reducing menorrhagia in VWD. We powered our trial based 
on the primary endpoint of a 40-point greater reduction in PBAC when treated with rVWF compared to 
TA.  Assuming intent-to-treat (ITT) analyses, a two-tailed alternative hypothesis with type I error rate of 
0.05, a 4-period 2-group (AABB/BBAA) crossover design, an estimated between-subject standard 
deviation of 63 points and an estimated within-subject standard deviation of 100 points, a total of N=60 
patients will provide 84% power to detect a difference in improvement of 40 points or more between 
rVWF and TA.  The sample size was inflated to N=66 to account for an expected dropout rate of 10% or 
less. Refer to SAP for more details. 
 
Reviewers of the NHLBI 2009 State of the Science (SoS) Hemostasis and Thrombosis panel considered the 
continuous outcome a limitation and suggested using percent reduction as a more clinically meaningful 
endpoint. A disadvantage of this approach is that it results in a higher sample size, and, although a 
dichotomous outcome is clinically relevant, the sample size is too high to achieve in this rare disease.  
 
The difference of 40 points used in our sample size determination was deemed clinically meaningful and 
feasible, based on six trials in which 95% or more of women receiving rVWF had >50% reduction in PBAC 
(10, 11), and the belief that smaller effects between groups might not change clinical practice or patient 
behavior, e.g. adopting IV dosing or higher cost treatment.  
  
9.3 
POPULATIONS FOR ANALYSES 
 
The full analysis set will be based on an intention-to-treat (ITT) analysis, which will comprise all 
participants who have been randomized to either of the two crossover sequences (AABB/BBAA), 
regardless of length of follow-up or actual intervention received. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Descriptive statistics will be presented as means and standard deviations for continuous variables and 
sample proportions for categorical variables.  All descriptive statistics will be accompanied by 95% 
confidence intervals.  For inferential tests, a two-tailed p-value <0.05 (type I error rate of 0.05) will 
determine statistical significance; the confidence level for confidence intervals will be set at 95%.  
Covariates and potential remedies to violations of assumptions underlying statistical procedures are 
specified in the SAP. 

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9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint is the continuous score on the pictorial blood assessment chart (PBAC), a validated 
measure of menstrual blood loss described in sections above.   
The primary endpoint, PBAC score, will be compared between rVWF and TA using a linear mixed model 
(LMM) fit via restricted maximum likelihood estimation (REML) to account for repeated measures (65). 
The distribution of the outcome will be checked for departures from the assumptions of linear mixed 
modeling, such as normality, and a transformation will be employed as necessary. Treatment and 
menstrual cycle will be included as fixed effects in the model.  Though we expect no crossover effect, we 
will assess this by testing whether a treatment-by-cycle interaction term is significant.  If the interaction 
is not significant, we will assume no carryover effect and remove the interaction term from the model.  
Baseline PBAC score will be included as a covariate. The intercept will be allowed to vary randomly to 
account for subject-level variability of the outcome at baseline. The Kenward-Roger method for 
calculating degrees of freedom will be used to improve small-sample performance (65). The linear mixed 
model will allow for unbiased estimates of treatment effects and the utilization of all data under the 
intention to treat (ITT) principle and the assumption that data are missing at random (MAR). This approach 
will provide least-squares estimates of the mean reductions in bleeding score on each treatment and allow 
for statistical comparison of the difference between them. Additional details may be found in the SAP. 
As a preventive measure, we will make every attempt to document all reasons for missing data. In 
addition, baseline characteristics will be compared between participants who do and do not withdraw 
from the study as a way to assess the impact of missing information and attrition.  For missing data from 
lost or incomplete diaries, HTC nurses will obtain data retrospectively at study visits 1-2 months later, for 
which recall is excellent.  We will investigate the reasons for intermittently missing data (misses an 
assessment but comes back) and dropouts, and use the likelihood-based procedure if "missing at random" 
(MAR) is confirmed. If the missing-ness is found to be non-ignorable (missing not at random), we will 
consider joint or shared parameter models. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary endpoints will include continuous and categorical measures described in sections above, 
such as: a) frequency of menorrhagia unresponsive to study drugs or rescue, recorded by patient diary; b) 
cycle severity rating (CS); c) cycle length (CL); and d) quality of life questionnaires and satisfaction survey. 
In addition, response to study treatment will be compared with VWF assays and VWF genotype. 
Continuous secondary outcomes, including cycle severity, quality of life, and coagulation measures, will 
be analyzed with multivariable linear mixed models fit via maximum likelihood using the same approach 
as for the primary outcome. The same fixed and random effects will be included in secondary outcome 
models.  Multivariable generalized linear mixed models (GLMMs), including the same fixed and random 
terms as the primary outcome model, will be used to analyze categorical secondary outcomes. Least-

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squares estimates of treatment effects will be obtained to determine if significant differences in outcomes 
exist between rVWF and TA.  
 
 
9.4.4 SAFETY ANALYSES 
Safety Analyses. Safety endpoints, including bleeding severity (CS), cycle length (CL), and frequency of 
menorrhagia unresponsive to study drugs or rescue dose, are secondary endpoints, and will be analyzed 
as described above.  AEs will be coded by “Cancer Therapy Evaluation Program: Common Terminology 
Criteria for Adverse Events” (CTCAE) (49), calculated (e.g., each AE will be counted once only for a given 
participant), presented (e.g., severity, frequency, and relationship of AEs to study intervention will be 
presented by System Organ Class (SOC) and preferred term groupings) and will include for each AE the 
start date, stop date, severity, relationship, expectedness, outcome, and duration will be analyzed by 
descriptive statistics, by study subject and study arm, as described above.  Safety Stopping Events, below, 
enumerate specific Adverse events leading to premature discontinuation from the study include: 
The Safety Stopping Events include: 
1. Uncontrolled Menstrual Bleeding 
 
Stopping Rules: The DSMB will define stopping of the trial after individual evaluation of 
uncontrolled menstrual bleeding.  
Suspension Rules: A subject develops uncontrolled menstrual bleeding despite or in association 
with the administration of rVWF or TA, defined as >2 gm% fall in hemoglobin from baseline, 
and/or requirement for RBC transfusion and/or cardiopulmonary resuscitation. 
       2.    Thrombosis   
Stopping Rules: The DSMB will define stopping of the trial after individual evaluation of               
thrombosis. 
Suspension Rules: A subject develops severe, catastrophic, or life-threatening thrombosis 
associated with rVWF or TA, which requires cessation of study drug dosing, with the exception of 
intravenous (IV) infusion site thrombophlebitis. 
3. Grade 2-5 Allergic Reaction 
Stopping Rules: The DSMB will define stopping of the trial after individual evaluation of a grade 2 
or greater allergic reaction.  
Suspension Rules: A subject develops anaphylaxis or a grade 2 or greater allergic reaction 
associated with rVWF or TA, defined by CTCAE grading. 
• 
Grade 2 
Intervention or infusion interruption indicated, responds promptly to               
symptomatic treatment (e.g. antihistamines, NSAIDS, narcotics); prophylactic 
medications indicated for < 24 hours  
• 
Grade 3        Prolonged (e.g. not rapidly responsive to symptomatic medication and/or brief  
 
 
interruption of infusion); recurrence of symptoms following initial improvement,  
                             hospitalization indicated for clinical sequelae (e.g. renal impairment, pulmonary  
                             infiltrates)                         

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• 
Grade 4      Life-threatening consequences, urgent intervention indicated 
• 
Grade 5      Death 
   
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
As described in the SAP, baseline characteristics will be presented using conventional descriptive statistics 
such as means, standard deviations, counts and proportions. All descriptive statistics will be accompanied 
by 95% confidence intervals.  Baseline comparisons will be performed between the two sequences of 
treatments (AABB versus BBAA) using two-sample t-tests for interval data, chi-squared tests for 
categorical variables, or their nonparametric counterparts.  
  
9.4.6 PLANNED INTERIM ANALYSES  
Not applicable. 
9.4.7 SUB-GROUP ANALYSES 
 
Not applicable. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable. 
 
9.4.9 EXPLORATORY ANALYSES 
    
Exploratory Analysis: This study will have one exploratory analysis, a cost-effectiveness analysis. In this 
analysis, the primary cost outcome will be menorrhagia treatment costs from the health care sector 
perspective, i.e., health system costs for implementing each prophylactic treatment and other direct costs 
associated with menorrhagia care, including medical/surgical costs (all primary, secondary, and tertiary 
care costs) associated with menorrhagia treatment. We will determine 1) the incremental cost to the 
health system of implementing the menorrhagia prevention interventions, including medication and 
infusion costs; and 2) all other menorrhagia care costs not related to the interventions (i.e., all outpatient 
visits and hospitalizations). The analysis will use costs in 2017 US dollars.  
In addition, as a secondary cost outcome, we will determine costs from a societal perspective, which will 
include the health care sector costs above plus indirect costs resulting from days lost from work or school.  
We will collect data pertinent to costs (costs of TA, rVWF, iron infusion, and RBC transfusion; ER/hospital 
care episodes; days lost from work/school). Intervention and event costs for each intervention will be 
estimated using Centers for Medicare and Medicaid Services (CMS), Healthcare Cost and Utilization 
Project (HCUP), and Bureau of Labor Statistics databases. Medication costs will be estimated using 
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The primary effectiveness term will be quality adjusted life years, the product of the quality of life utility 
value of a health state and the time spent in that state. Utilities measure preferences for health states 
and range from 0 (death) to 1 (perfect health). Utilities can be derived from a variety of quality of life 
measures, or measured directly by questionnaires or other techniques. In our analysis, intervention-
specific utilities will be derived from SF-36 scores using a validated algorithm.  We will calculate 95% CIs 
around cost and effectiveness estimates and conduct sensitivity analyses to examine the robustness of 
our assumptions. We will assess intervention program value using incremental cost, incremental 
effectiveness, and incremental cost effectiveness ratios.  
In the primary analysis, differences in healthcare sector costs and effectiveness between interventions 
will be compared via incremental cost-effectiveness ratios, yielding incremental costs per quality 
adjusted life year (QALY) gained when comparing one intervention to the other. Secondary analyses will 
similarly compare societal perspective costs and effectiveness between interventions. In this analysis, 
work/school absence cost will be calculated by multiplying days absent by the US average daily wages 
for nonfarm production workers, using US Bureau of Labor Statistics data.  
The robustness of cost-effectiveness analysis results will be tested using 1-way sensitivity analyses and 
probabilistic sensitivity analysis. In 1-way sensitivity analyses, all parameter values will be individually 
varied to test their effect on cost-effectiveness results. In the probabilistic sensitivity analysis, all model 
parameters will be simultaneously varied over distributions 5000 times, with results summarized using a 
cost-effectiveness acceptability curve, which shows the likelihood that interventions are favored over a 
range of quality adjusted life year dollar value (or acceptability) thresholds, and depict the probability 
that one strategy is less costly and more effective than the other (i.e., “dominant”). In the US, there is no 
established cost-effectiveness acceptability criterion; $50,000-$150,000 per quality adjusted life year 
gained is a commonly cited range for justifiable costs based on actual US healthcare spending. 
 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATION 
 
10.1.1 INFORMED CONSENT PROCESS 
 
In obtaining and documenting informed consent, the investigator must comply with applicable regulatory 
requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should adhere to ICH GCP. Prior 
to the beginning of the trial, the investigator should have the IRB’s written approval for the protocol and 
the written informed consent form(s) and any other written information to be provided to the 
participants.  
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 

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Consent forms that describe in detail the study intervention, study procedures, and risks will be given to 
the study subject. Written documentation of informed consent is required prior to starting or 
administering a study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the subject and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the subject’s comprehension of the purposes, procedures, 
and potential risks of the study and of their rights as research participants.  Subjects will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. The subjects 
should have the opportunity to discuss the study with their family or surrogates or think about it prior to 
agreeing to participate. The subject will sign the informed consent document prior to any procedures 
being done specifically for the study. Subjects must be informed that participation is voluntary and that 
they may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to study subjects for their records. The informed consent process will be 
conducted and documented in the source document (including the date), and the form signed, before the 
participant undergoes any study-specific procedures. The rights and welfare of the subjects will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, University of Pittsburgh, 
participating institutions, and NHLBI.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor 
and will provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 

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Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Study participation and related data will be protected to maintain confidentiality. There is a possibility 
that the subject’s personal information or genetic material could become generally known. This 
information could impact future insurability, employability, or reproduction plans, or have a negative 
impact on family relationships, and/or result in paternity suits or stigmatization. In order to reduce risks 
of disclosure or breach of confidentiality, the research related documents, blood samples and clinical 
information stored in subject research files will be assigned an alphanumeric (letters and numbers) 
identifier (that do not contain personal identifiers). For this study, a linkage key for linking this number 
and the subject’s name will be kept at HTCs under lock and key by the principal investigator and research 
staff. Any publication arising from this study will not contain names or other identification unless study 
subjects grant permission in another signed consent.   
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsors and their interventions. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may inspect 
all documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study, but 
they will be under the same strict confidentiality requirements. The study participant’s contact 
information will be securely stored at each clinical site for internal use during the study. At the end of the 
study, all records will continue to be kept in a secure location for as long a period as dictated by the 
reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the University of Pittsburgh Data Coordinating Center. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their research data 
will be identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by the Data Coordinating Center research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at the 
CRHC DC Data Coordinating Center. 
 

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10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the University of Pittsburgh Center for Health 
Care Data Center (CRHC DC) Data Coordinating Center (DCC). After the study is completed, the de-
identified, archived data will be transmitted to and stored at the University of Pittsburgh CRHC DC 
Repository, for use by other researchers including those outside of the study. Permission to transmit data 
to the University of Pittsburgh CRHC DC Repository will be included in the informed consent.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples will be stored at the University of North Carolina Francis Owen Blood Research 
Laboratory, Chapel Hill, NC with the same goal as the sharing of data with the University of Pittsburgh 
CRHC DC Repository. These samples could be used to research the causes of von Willebrand disease and 
its complications and other conditions for which individuals with congenital bleeding disorders are at 
increased risk, and to improve treatment. The CRHC DC Data Repository will also be provided with a code-
link that will allow linking the biological specimens with the phenotypic data from each participant, 
maintaining the blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to bio-
sample storage may not be possible after the study is completed.  When the study is completed, access 
to study data will be provided through the University of Pittsburgh CRHC DC Repository and samples will 
be provided through University of North Carolina Francis Owen Blood Research Laboratory, Chapel Hill. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Study Organization and Administration.  The Clinical Coordinating Center (CCC) for this multi-site clinical 
trial will be headquartered at the University of Pittsburgh under the direction of Dr. Ragni, PI. The Data 
Coordinating Center (DCC) for this multi-site clinical trial will the Clinical Trials and Data Coordinating 
Center (CCDC), part of the Center for Research on Health Care Data Center (CRHC DC), University of 
Pittsburgh under the direction of Dr. Doris Rubio, Co-Investigator.  Dr. Ragni, an expert in VWD, will direct 
and be responsible for the scientific and clinical performance of the trial, and regulatory aspects of the 
trial, including NHLBI and IRB submissions. She will work closely with Dr. Rubio, an expert in statistics and 
trial design, who will oversee data management and statistical plan and analyses. The CCC and DCC will 
analyze the data, prepare publications, and jointly monitor the conduct of the study, including 
recruitment, data quality, and protocol compliance and adherence. The CCC PI and DCC PI will work 
collaboratively to assure the trial is completed on-time and on-budget. They will meet weekly or biweekly 
to manage and monitor the trial, review enrollment, assess milestones, identify barriers, and implement 
strategies and approaches to resolve them in a timely fashion.  
Key Roles and Study Governance 
Principal Investigator 
Medical Monitor 

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Margaret V. Ragni, MD, MPH 
Professor of Medicine and Clinical Translational 
Science, Department of Medicine 
Amy Shapiro, MD 
Director, Indiana Hemophilia & Thrombosis 
Center 
Pediatric Hematology 
University of Pittsburgh  
School of Medicine 
Indiana University  
Health University Hospital 
Hemophilia Center of Western PA (HCWP)  
3636 Boulevard of the Allies 
Pittsburgh PA 15213-4306 
Indiana Hemophilia & Thrombosis Center, Inc. 
8326 Naab Road 
Indianapolis IN 46260 
412-209-7288 
317-871-0000 
ragni@pitt.edu  
ashapiro@ihtc.org  
   
The CCC PI and DCC PI will serve on and be advised by the Executive Committee (EC), which will also 
include the NHLBI program officer, Nahed El Kassar, MD, PhD, who will meet monthly to set policy and 
monitor trial operations, review project-wide issues and formulate policy regarding the conduct of the 
trial. 
The CCC PI and DCC PI will also serve on and be advised by the Steering Committee (SC) which will also 
consist of 10 site HTC MDs rotating staggering 3-year terms, and a Gynecologist Consultant. The SC will 
set policy, make decisions, and meet quarterly to review and discuss site (HTC) problems and protocol 
barriers, and monitor and advise on trial progress, as well as safety and efficacy outcomes. 
The Investigator Consortium Network of approximately 25 HTC MDs and nurse coordinators will 
participate in monthly conference calls and advise the CCC PI and DCC PI on screening, enrollment, HTC 
problems and barriers, and clinical and safety problems that arise. 
The trial will be monitored by an NHLBI-appointed Data and Safety Monitoring Board (DSMB), including 
hematologists, statisticians, and clinical trial experts, who will monitor trial progress and safety, review 
adverse events and severe adverse events and adjudicate safety and efficacy endpoints and study 
stopping rules.   
10.1.6 SAFETY OVERSIGHT 
  
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including experts in hematology, hemostasis, women’s health, 
and statistics.   Members of the DSMB should be independent from the study conduct and free of conflict 
of interest, or measures should be in place to minimize perceived conflict of interest.  The DSMB will meet 
at least semiannually to assess safety and efficacy data on each arm of the study. The DMSB will operate 

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under the rules of an approved charter that will be written and reviewed at the organizational meeting of 
the DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The 
DSMB will provide its input to the CCC, DCC, Executive Committee, Steering Committee, and National 
Institutes of Health staff. 
Data and Safety Monitoring Plan (DSMP). An external Data and Safety Monitoring Board (DSMB) 
consisting of members appointed by the National Heart, Lung, and Blood Institute (NHLBI) will monitor 
the trial, advise the National Institutes of Health (NIH) Program Officer and provide input to the Steering 
Committee. The DSMB will be composed of nationally recognized experts in hematology, women’s health, 
or in clinical trials. The DSMB will review the study protocol and provide NHLBI with recommendations. 
Recruitment will be initiated after the NHBLI receives the DSMB recommendation and approves the study 
protocol. Throughout the course of the trial, the DSMB will review recruitment, retention, data 
completeness, protocol deviations, adverse events (AEs), severe adverse events (SAEs) and unexpected 
problems (UPs) on a semi-annual basis and will provide written recommendations to NHLBI. 
Local Data Safety Monitoring Committee. The local Data Safety Monitoring Committee for this study will 
include the local PI and Clinical Coordinating Center (CCC) PI, Dr. Ragni, and the nurse coordinator(s), who 
will meet at least bi-weekly and be responsible for ongoing monitoring all recruitment, data collection and 
subject confidentiality procedures at this site. Subjects will be closely monitored by the PI, research and 
clinical staff to ensure subject safety and to ensure that procedures are in place to maintain privacy and 
confidentiality, progress of study, integrity of the data, procedure reviews and for discussion of pertinent 
scientific literature or events which could affect the benefit to risk ratio. All serious and unexpected 
adverse events and/or major breaches of confidentiality will be reported to the sponsor and to the IRB 
according to regulations outlined in the IRB Reference Manual for the Use of Human Subjects.  All AE’s, 
SAE’s generated from the HTCs will be sent following reporting guidelines to the DCC who will forward to 
the NIH (see table 9.4.3). A report summarizing the above local and central DSMP activities will be 
submitted to the IRB at the time of annual renewal.  
10.1.7 CLINICAL MONITORING 
 
Adverse Event Monitoring. Adverse events will be monitored in four distinct ways: 1) the DSMB will 
review all reported adverse events and monitor the incidence rates on a semi-annual basis, 2) the 
expedited review of unexpected SAEs related to the protocol and unanticipated problems (UP), 3) all 
study outcomes will be evaluated by assigned treatment group on semi-annual basis, and 4) the formal 
statistical interim monitoring of the efficacy of the primary outcome by assigned treatment group on an 
annual basis. If unexpected safety concerns arise from the trial data or from external research or 
literature, then safety data reporting will be expanded and examined on an ad-hoc basis. The Clinical 
Coordinating Center (CCC) and the Data Coordinating Center (DCC) will work with the NIH and with the 
DSMB to ensure that the board members have sufficient information to comprehensively monitor 
patient safety throughout the trial. The DSMB may advise early termination of the trial for safety 
reasons, efficacy of the primary outcome or other modifications to the protocol. 

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Because approximately 25 sites across the U.S. will participate in this trial, there will be no on-site 
monitoring. Instead, monitoring of all records and study subjects will be performed via the University 
of Pittsburgh CRHC DC electronic database, monthly conference calls with CCC, DCC, and approximately 
25 study co-investigators and coordinators, and annual investigator-coordinator study meetings held 
during the American Society of Hematology annual meeting which most co-investigators attend.   
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).  
 
The remote monitoring for this study will be performed by The Data Coordinating Center (DCC). 
The DCC electronic Master Regulatory File (eMRF) will be utilized to remotely monitor the 
regulatory and study team essential documentation. Each principal investigator will identify a site 
“registrar” to manage the upload of required information into the eMRF. Please refer to the CCDC 
Clinical Monitoring Plan (CMP) for additional information related to the eMRF. 
Remote or centralized monitoring will be conducted prior to all site activation and throughout the 
study for each study center, the frequency of remote visits will be based on the developed 
monitoring strategy taking into consideration: enrollment status, data quality, protocol 
compliance, and the prescribed amount of data to be monitored according to the monitoring plan.  
Irrespective of other factors, the site will be monitored at least once per year and conducted 
according to the CCDC CMP (Attachment). 
Prior to each remote visit, the DCC will issue a letter notifying the investigator of the scheduled 
remote audit. The document will be disseminated to the CCC PI, site PI and the study team. The 
following is a summary of DCC remote audits that will take place: 
o Site Initiation remote visit (SIRV):  
▪ 
The SIRV will be scheduled according to site readiness with regard to institutional 
approvals and study team availability.  
▪ 
The DCC PI, Sr. Administrator and regulatory monitor and CCC National 
Coordinator will conduct the web-based remote site initiation visit with multiple 
sites/study teams attending. The presentation will include study team training in 
the use and application of the eSYSDM specific to the study. A detailed 
description of topics to be reviewed during the training are outlined in the CCDC 
CMP.  
▪ 
The remote visit will be scheduled in advance. A confirmation letter with meeting 
agenda will be issued prior to the web teleconference giving notice of the conduct 
of a remote audit of the eMRF content.  
▪ 
Pre-scheduled teleconferences with individual site study teams will take place 
after the web training. These site-specific teleconferences are designed to discuss 
eMRF audit findings, discuss site action items and attend to site specific concerns. 

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▪ 
Site Principal Investigator and study team attendance to the SIRV web conference 
is mandatory. The site PI and his/her lead coordinator are to attend the post SIRV 
teleconference to discuss site specific concerns. 
Site Activation Approval- The DCC will approve site activation once all audit 
findings confirm site readiness to enroll subjects. The activation of the site will be 
formalized by the DCC issuance of a site activation letter sent to the CCC and site 
Principal Investigators. 
o Remote audit of informed consents 
▪ 
The DCC monitor will review the informed consent (IC) document for 100% of 
subjects enrolled in the study. 
▪ 
In the event of amendments during the course of the trial, all subject re-consent 
will also undergo the 100% consent audit. 
▪ 
Study coordinators will upload the IC via the study web portal.  
▪ 
A narrative note describing the informed consent process is required for any 
research study that involves the evaluation of a research intervention (FDA 21 
CFR 312.62). This narrative document will undergo DCC audit concurrent with IC 
review. 
o This audit process is described in detail in the CCDC CMP. Remote audit of study files 
▪ 
100% of the study files for the first 1-2 subjects enrolled at each study center will 
be audited at the time of randomization and at study completion.  
▪ 
At a minimum, the following data will be monitored: 
• 
Eligibility, Inclusion/exclusion criteria 
• 
Source documentation to support diagnosis, inclusion/exclusion criteria 
• 
Verification protocolized study procedures are completed in keeping 
with study directives. 
• 
Review of drug accountability and concomitant medications 
• 
100% review of reported SAE  
• 
Confirmation of PI review and electronic signature on all required eCRF 
forms. 
• 
Review of system content to identify errors, omissions, discrepancies 
• 
Review of study team compliance with DCC-directed action items 
▪ 
The process of study subject file audit involves provision of de-identified hard 
copy upload into the CCDC audit portal. These procedures are described in the 
CMP training.  
▪ 
eMRF review- A review of the eMRF will accompany the audit of the 1-2 study 
subjects at the completion of their study participation to ensure the validity of all 
regulatory and essential documents. 
▪ 
Audit findings summary report 
• 
The DCC monitor will document the audit findings in a summary report 
within 14 days of the audit and disseminate the report to the CCC and 
site PI.  

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All identified action items must be completed within 30 days of the audit report submission date.  
o For-Cause Remote Audits 
• 
Remote audits will be conducted if the DCC identifies multiple discrepancies in 
data entry, delayed response to DCC requested action items, high rate of protocol 
deviations or site findings that are inconsistent when compared to the 
performance of other study sites. 
The Site PI will be contacted by phone to discuss the concerns and email notification 
of the date of the for-cause remote audit will be circulated. 
o Remote Close-out visit 
• 
Close-out visits may be conducted at study completion or earlier in the case of 
study termination by the IRB, Data Safety Monitoring Board (DSMB) or FDA. 
• 
A final closeout audit of the eMRF will take place to ensure all regulatory and 
essential documents are incorporated as expected. 
During the course of the study, data checks are completed to ensure no missing 
data is present. At close out, an audit of all subject data fields will be reviewed, 
any outstanding data will be identified and requests to complete missing data will 
be sent to the study team to rectify. 
• 
Notification of remote audit findings The Principal Investigators from the CCC and the audited 
clinical site will be provided copies of monitoring reports within 14 business days of the remote 
visit(s). Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The 
CMP describes the responsibilities of the study team with regard to provision of essential 
documentation, the process employed by the DCC to conduct the monitoring, the frequency with 
which the monitoring will be completed, the monitoring to be performed, and the process 
whereby monitoring reports are disseminated to investigators. 
    
  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  An individualized quality management plan will be developed 
to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP).  
 

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The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The Data Coordinating Center (DCC) will oversee all aspects of data management. With the consultation 
of the DCC, the PI and coordinator will develop an operations manual to standardize all procedures and 
staff training in areas such as patient recruitment, measurement, assessment, and data entry, 
management, and security. The DCC coordinator will conduct the initial web-based system training 
sessions for study teams via online teleconferences. Online access to video training that supports the 
initial training will be available during the course of the trial. All subsequent training sessions for new 
study personnel or retraining related to the web-based system or study procedures will be the 
responsibility of the CCC national coordinator. The DCC will provided consultant support of the CCC 
coordinator to guide new training sessions and for those study teams that exhibit a need for additional 
education.  
The DCC will create an electronic System for Data Management (eSYSDM), based on detailed study 
protocols and requirements that includes an electronic case report form and a tracking system, with the 
capability to incorporate EHR. The eSYSDM is developed using .NET 2.0 to create the interface and SQL 
for the database.  The DCC will work closely with investigative team and other study personnel to ensure 
that protocols are being followed, data integrity and confidentiality are maintained, and that the data 
contains a minimum amount of missing data. All study files residing in designated network folders will be 
backed-up daily and archived weekly. The weekly archived files are maintained for 1 year until the data 
are erased. All study subjects will be assigned unique study identifiers that will appear on all data 
collection instruments, electronic media, documents, and files used in the statistical analysis and 
manuscript preparation. Only authorized team members will have access to personal information needed 
for tracking and informed consent. Other data quality assurance measures will include detailed 
documentation of computer operations and data editing procedures and regular meetings with project 
staff to review any changes in procedure. The DCC also has specific data quality measures that will be 
implemented.  These include data verification, built in data validation mechanisms such as logic and out 
of range data checks, and repeated evaluation of the data collection and entry process. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
All records must be maintained for at least seven years. Permission from the Coordinating Center is 
required prior to record destruction. 

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10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.2 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations 
within 7 working days of identification of the protocol deviation, or within 7 working days of the scheduled 
protocol-required activity.  All deviations must be addressed in study source documents, reported to the 
NHLBI Program Officer and the Center for Clinical Trials and Data Coordination.  Protocol deviations must 
be sent to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
The Executive Committee will be responsible for developing publication procedures and resolving 
authorship issues.  The specific grant, U01-A1 HL 133815, is in compliance with: 
• 
The NIH Public Access Policy, the NIH Policy on the Dissemination of NIH-Funded Clinical Trial 
Information, The Food and Drug Administration Amendments Act of 2007 (FDAAA), Clinical Trials 
Registration and Results Information Submission rule, 
• 
The NIH Data Sharing Policy 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
  
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial has been registered at ClinicalTrials.gov, NCT02606045, and results information from this 

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trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in 
peer-reviewed journals.  Researchers will be able to locate and access data and/or other specimens from 
the VWDMin Trial by formal application which can be found on the BioLINCC website, 
https://biolincc.nhlbi.nih.gov. This repository has data access policies and procedures in place that will 
provide data access to qualified researchers, consistent with NIH data sharing policies and applicable laws 
and regulations. Once an investigator application request is approved by NHLBI, and upon receipt of a 
Research Materials Distribution Agreement, data will be transferred by secure transfers through the 
BioLINCC website. For biologic specimen requests, upon NHLBI approval of an investigator application 
request, and with evidence of funding and adequate facilities and expertise to perform the proposed 
research, BioLINCC will request that the repository prepare and ship the requested biologic specimens. 
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS), single 
nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  The study leadership in 
conjunction with NHLBI has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported dualities of 
interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
10.2.1 COSTS AND PAYMENTS 
Research Study Costs.  No costs will be incurred by the subject for their participation in this study for 
research procedures. NIH will compensate HTCs for research procedures as outlined in the contract and 
budget. IRB preparation costs will be covered, along with research procedures, including screening visits, 
blood draws for local and central laboratories, blood processing, shipping, lab assays, and HTC charges 
and services related this study protocol. Pending notification of funding, an NIH-contracted pharmacy 
will provide rVWF and TA for administration in this study. Research blood draw kits will be prepared by 
the CRHC DC, according to the linked randomization allocation codes for each study subject, and 
shipped to each HTC for enrolled subjects.  
 Research Study Payments. Subjects will receive compensation for participation in this study, to help 
defray the cost of meals, travel, and time lost from work.  There will be no additional costs to study 

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subjects for participation in this study beyond the charges for routine medical care and administration of 
medications. The study is pending funding by NHLBI. Compensation is based on visits and frequency of 
blood draws. Subjects will receive $100 per visit for up to 4 visits during the 24-week trial, including 
screening visit and 3 study visits, the latter of which includes the end-of-study visit. If subjects do not 
complete any part of the scheduled study days, compensation for missed visits will not be made. A 
check will be mailed to each subject upon completion of the study, at least within 4-6 weeks of end of 
study. If, for whatever reason, subjects complete part but not all of the study, the terms of payment will 
be determined by the number of visits completed.   
10.2.2 HUMAN SUBJECTS 
General Characteristics - Minority Inclusion and Non-Discriminatory Statements. Females age 13-45 
years of age with von Willebrand disease, defined by VWF:RCo <0.50 IU/ml (historic or current), previous 
bleeding history, and who have menorrhagia and a PBAC >100 in at least one of the two preceding 
menstrual cycles, and cared for at one of the approximately 25 centers participating in this trial will be 
eligible for study. It is estimated that up to 60 eligible subjects (inflated to 66 to anticipate dropout) will 
be enrolled (Table 1). Children under 13 will be excluded as most have not reached regular menses. We 
shall attempt to recruit subjects in respective proportion to these demographics. All subjects will be 
screened prior to enrollment for history and laboratory data confirming a VWD diagnosis. Written 
informed consent will be obtained from all subjects at the screening visit. Once eligibility is confirmed, 
visit 1 will be defined as start of enrollment. It is estimated that the HCWP site will screen and enroll 2-5 
subjects locally, and up to 60 (inflated to 66 to anticipate dropout) nationally. The requirement for PBAC 
>100 based in at least one of the two preceding menstrual cycles will also serve as baseline menstrual 
severity for comparison with study drugs.  
Inclusion of Children.  As this study concerns menstrual cycle bleeding, only women, 13-45 years of age 
will be included. Children under 13 are excluded from participation as most have not reached regular 
menses. 
10.2.3 QUALIFICATIONS 
Qualifications of Investigators. Dr. Margaret Ragni is a Professor of Medicine, Division 
Hematology/Oncology, and Director of the Hemophilia Center of Western PA, and has conducted 
numerous clinical research studies at the University, investigator-initiated and in collaboration with the 
CDC, FDA, NIH, pharmaceuticals. She is an expert in the area of von Willebrand disease, including 
pioneer studies of new agents, including rVWF in clinical trials, multicenter genotype phenotype VWD 
studies, development of better predictors of VWD in children, and developing better therapies for 
menorrhagia in women with VWD. 
Dr. Craig Seaman is an Assistant Professor of Medicine, Division Hematology/Oncology, and Assistant 
Director of the Hemophilia Center of Western PA. He collaborates with Dr. Ragni on clinical research 
studies, and is focusing on investigator-initiated studies in hypertension and cardiovascular disease in von 
Willebrand disease.  

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
CCC 
Clinical Coordinating Center 
CCDC 
Center for Clinical Trials and Data Coordination 
CFR 
Code of Federal Regulations 
CL 
Cycle Length 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CRHC DC 
Center for Health Care Data Center 
CS 
Cycle Severity Rating  
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
eCRF 
Electronic Case Report Forms 
eSYSDM 
Electronic System for Data Management 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HCWP 
Hemophilia Center of Western Pennsylvania 
HIPAA 
Health Insurance Portability and Accountability Act  
HTC 
Hemophilia Treatment Center 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NHLBI 
National Heart Blood Lung Institute 
OHRP 
Office for Human Research Protections 
PBAC 
Pictorial Blood Assessment Chart 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
rVWF 
Recombinant Von Willebrand Factor 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TA 
Tranexamic acid, Lysteda 
UP 
Unanticipated Problem 
US 
United States 
VNA 
Visiting Nurses Association  
VWD 
Von Willebrand Disease 
VWDMin 
Von Willebrand Disease Minimize Trial 
VWF 
Von Willebrand Factor 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
03.19.18 
Conversion of protocol document to 
NIH template 
NHLBI DSMB reviewed for 
initial submission 
2.0 
07.17.18 
Amended content for administrative, 
discrepancy, and formatting 
corrections; eligibility update 
Administrative, discrepancy, 
formatting corrections; 
eligibility update for renal 
disease exclusion 
3.0 
08.16.19 
Inclusion criteria have been relaxed 
to include age 16-45 and VWD of any 
type.; and increasing participating 
sites to approximately 25. 
As enrollment is sluggish, there 
was agreement by NIH and sites 
to relax inclusion criteria and 
increase the number of 
participating sites. 
4.0 
12.11.19 
Inclusion criteria have been relaxed 
to include age 13-45 
Many young girls start on COCs 
(combined oral contraceptives) 
and are ineligible for our study. 
In this study, these young girls 
have the opportunity to try two 
new agents for two cycles each, 
at no cost. 
5.0 
02.24.20 
Exclusion criteria revised to clarify 
use of hormones (other than 
progesterone-only), or combined 
oral contraceptives, and 
contraceptive implants in past 3 
months. 
While hormonal contraception 
has been a contraindication 
(when using lysteda, and 
because they increase VWF), 
progesterone alone 
contraception does not increase 
thrombotic risk nor is it a 
contraindication with Lysteda. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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