Conditions: Hemophilia A With Inhibitor Hemophilia A
Keywords: inhibitor Factor VIII inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
The primary goal of the INITIATE trial is to compare the clinical outcome of individualized lot selection to random lot selection utilizing one plasma-derived von Willebrand factor (VWF)/coagulation factor (FVIII) complex concentrate for immune tolerance induction (ITI) in subjects with congenital Hemophilia A, FVIII activity ≤2%, and a historical high-titer inhibitor \[≥5 Bethesda Unit (BU)\].

Detailed description:
Participants will be randomized on a one-to-one basis between one of two study arms, individualized lot selection (alternative treatment arm) and random lot selection (standard treatment arm, current US clinical practice in ITI). Study sites, participants, and investigators will be blinded to the treatment status assigned.

Alternative treatment arm:

Half of the participants will be randomized to blinded individualized lot selection for ITI. The target initial dose of FVIII for ITI is \~200 IU/kg/day intravenously. The suggested maximum dose is 20,000 IU/day. Investigators may adjust the dose to a minimum dose of 150 units/kg if infusion volume is not feasible in patients without central venous access or in patients with von Willebrand factor levels \>250%. Splitting dose into two infusions per day must be approved by the Steering Committee, and if approved, will be considered a protocol deviation. Wilate® will be the VWF/FVIII complex concentrate (Octapharma USA, Inc., U.S. License No. 1646) prescribed for ITI.

Individualized lot selection will be performed according to a modified Oxford method in a central laboratory, by testing subject's plasma against 4-6 lots of Wilate® and selecting the one with the highest residual FVIII (lowest Oxford titer) activity remaining after incubation. The same lot will be used throughout the entire ITI course for each subject. If the selected lot is depleted prior to the completion of ITI, a second individualized lot selection will be performed using the original plasma sample provided at baseline.

Each Wilate® batch includes 1.6-1.8 million IU and is expected to last for about 3-57 months depending on the weight of the subject and prescribed dose.

Standard treatment arm:

The other half of the participants will receive random lot selection for ITI. The dose and concentrate used will be the same. Concentrate will be randomly selected from available Wilate® lots. The same lot will be used throughout the entire ITI course for each subject. If the random lot is depleted prior to the completion of ITI, a second lot will be randomly selected. In both cases the random lot will be tested against subject's plasma to measure the residual FVIII activity left after incubation but this result will not affect lot selection.

The primary hypothesis is that the time to negative inhibitor (\<0.6 BU) will be shorter with individualized lot selection compared to random lot selection and that this will impact monthly break-through bleeding and reduce costs.

Arms:
arm 1: Half of the participants will be randomized to blinded individualized lot selection for ITI. arm 2: The other half of the participants will receive random lot selection for ITI.

Interventions: intervention 1: Wilate
Intervention descriptions: intervention 1: Wilate® is a high-purity (i.e. 100 IU FVIII/mg total protein) pdVWF/FVIII complex concentrate.Wilate® possesses all the important features asked for in ITI, namely high purity, a very high pathogen safety profile, and an excellent protection of its FVIII by VWF - all achieved through unique, novel, and innovative techniques.

Protocol document:
Prot_SAP_000.pdf: 
  
 
 
 
 
 
 
 
 
 
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PROTOCOL 
 
INVESTIGATOR-DRIVEN RANDOMIZED CLINICAL TRIAL 
 
PROTOCOL TITLE: INdividualized ITI based on fviii(ATE) protection by VWF (INITIATE) 
 
Product: Wilate® 
 
Protocol Version: 3.0 
 
Protocol Date:  31-Jul-2018 
 
 
PRINCIPAL INVESTIGATORS: 
Jonathan Ducore, MD, MPH  
 
UC Davis School of Medicine 
2516 Stockton Blvd, TICON II  
Sacramento, CA  95817 
Phone: 916-734-2781 
E-mail: jmducore@ucdavis.edu 
 
Courtney Thornburg, MD, MS 
Rady Children’s Hospital San Diego 
University of California San Diego 
3020 Children’s Way, MC 5035 
Phone: 858-966-5811 
E-mail: cthornburg@rchsd.org 
 
Website: www.initiateusa.com  
 
GRANTOR: 
Octapharma USA, Inc. 
Waterfront Corporate Center 
121 River Street, Suite 1201 
Hoboken, NJ 07030 USA 
 
 
SPONSOR: 
The University of California, Davis School of Medicine 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
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COORDINATING CENTER: 
 
University of California, Davis Medical Center 
Clinical Trials Office 
2921 Stockton Blvd., Suite 1400 
Sacramento, CA 95817 
 
CLINICAL PROJECT MANAGER: 
Katrina Wheeler 
2921 Stockton Blvd., Suite 1400 
Sacramento, CA 95817 
Phone: 916-703-9197 
Pager: 916-816-3526 
E-mail: krimson@ucdavis.edu 
 
 
 


  
 
 
 
 
 
 
 
 
 
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SIGNATURE PAGE 
 
Title of protocol: INdividualized ITI based on fviii(ATE) protection by VWF (INITIATE) 
 
 
Sponsor Approval 
 
 
 
_______________________________ 
 
 
_______________________ 
Jonathan Ducore, MD, MPH  
 
 
 
Date 
Principal Investigator 
 
 
 
 
 
_______________________________ 
 
 
_______________________ 
Courtney Thornburg, MD, MS 
 
 
 
Date 
Principal Investigator 
 
 
 
INVESTIGATOR AGREEMENT 
 
By signing this page, I attest that I have read and understand the contents of Clinical Protocol 
INdividualized ITI based on fviii(ATE) protection by VWF (INITIATE) and any current 
amendments. I agree to adhere to the design, conduct, and reporting requirements of 
the study as stated in the clinical protocol and to my obligations to the Sponsor as described in 
the protocol and executed contracts between myself, my Institution, and the Sponsor. I also 
agree to adhere to any subsequent amendments to the clinical protocol.  
 
I understand that no deviations from this protocol may be made without the written permission of 
the Study Coordinating Center PI, except where necessary to eliminate immediate hazard(s) to 
trial subjects, or when the change(s) involve only logistical or administrative aspects of the trial. 
 
 
Investigator’s Signature: _______________________________________________________ 
 
Investigator’s Name: _______________________________________________________ 
 
Institution: _______________________________________________________ 
 
Date: _______________________________________________________ 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
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SYNOPSIS 
 
PROTOCOL TITLE: Individualized ITI Based on FVIII Protection by VWF (INITIATE) 
 
OVERVIEW: The primary goal of the INITIATE trial is to compare the clinical outcome of 
individualized lot selection to random lot selection utilizing one plasma-derived von Willebrand 
factor (VWF)/coagulation factor (FVIII) complex concentrate for immune tolerance induction (ITI) 
in subjects with congenital Hemophilia A, FVIII activity ≤2%, and a historical high-titer inhibitor 
[≥5 Bethesda Unit (BU)].  
 
TREATMENT ARMS: 
Participants will be randomized on a two-to-one basis between one of two study arms, 
individualized lot selection (alternative treatment arm) and random lot selection 
(standard treatment arm, current US clinical practice in ITI). Study sites, participants and 
investigators will be blinded to the assigned treatment arm. 
 
Alternative Treatment Arm: 
Two-thirds of the participants will be randomized to blinded individualized lot selection for ITI. 
The target initial dose of FVIII for ITI is 200 IU/kg/day intravenously. Wilate® will be the 
VWF/FVIII complex concentrate (Octapharma USA, Inc.; U.S. License No. 1646) prescribed 
during the trial.  A FVIII dose reduction will be used for subjects receiving Hemlibra®  (See 
Appendix IV for specifics). 
 
Individualized lot selection will be performed according to a modified Oxford method in a central 
laboratory, by testing subject’s plasma against 4-6 lots of Wilate® and selecting the one with the 
highest residual FVIII activity remaining after incubation (lowest Oxford titer). The same lot will 
be used throughout the entire ITI course for each subject. If the selected lot is depleted prior to 
the completion of ITI, a second individualized lot selection will be performed using the original 
plasma sample provided at baseline. 
 
At six months, participants in the standard treatment arm who still have an inhibitor titer >0.6 
may be switched to the alternative treatment arm.They will be treated as new participants who 
have failed prior ITI and a second individualized lot selection will be performed using the original 
plasma sample provided at baseline. 
 
Standard Treatment Arm:  
One-third of the participants will receive random lot selection for ITI. The dose and concentrate 
(Wilate®) used will be the same as that for the alternative treatment arm. Concentrate will be 
randomly selected from available lots. The same lot will be used throughout the entire ITI course 
for each subject. If the random lot is depleted prior to the completion of ITI, a second lot will be 
randomly selected. In both cases the random lot will be tested against the subject’s plasma to 
measure the residual FVIII activity after incubation. The results of this test will not be used for lot 
selection. 
 
OBJECTIVES: 
Primary Objective: The primary objective of the INITIATE trial is the time to achieve negative 
inhibitor (<0.6 BU) comparing individualized lot selection to random lot selection.  
 
Secondary Objectives: Secondary objectives of this study include the time to achieve partial 
and complete success, maintenance of inhibitor eradication, monthly break-through bleeding 


  
 
 
 
 
 
 
 
 
 
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rates, cost of ITI including cost of bypassing agents for bleeding control, and adherence to the 
ITI treatment regimen comparing the standard to the alternative therapy. The impact of inhibitor 
titer at start of ITI and during the course of ITI, including the peak titer of the inhibitor, will be 
investigated. Additionally, biologic assays will be performed to understand factors related to ITI 
success. 
 
HYPOTHESIS:  
The primary hypothesis is that the time to negative inhibitor (<0.6 BU) will be shorter with 
individualized lot selection compared to random lot selection.  
 
INCLUSION/EXCLUSION CRITERIA: 
 
Inclusion Criteria: Subjects must meet all of the following criteria to be eligible for enrollment into 
the study: 
1) Diagnosis of congenital Hemophilia A and baseline FVIII ≤2%. 
2) Weight ≥ 5 kg 
3) History of FVIII inhibitor titer ≥5 BU 
4) Current FVIII inhibitor titer ≥5 BU or  ≥0.6 BU and failed ITI defined by FVIII recovery 
<66% normal and half-life <6 hours  
5) Adequate venous access for daily concentrate infusions 
6) For participants <18 years, a parent or guardian willing and able to provide informed 
consent with verbal or written assent from the child if require by the local institution. 
For participants ≥18 years, a willingness and ability to provide informed consent from 
the subject. 
7) Ability to comply with study related treatments, evaluations, and follow-up. 
 
Exclusion Criteria: Subjects meeting any of the following criteria are ineligible for enrollment in 
the study: 
1) Acquired hemophilia 
2) Congenital or acquired bleeding disorder in addition to Hemophilia A 
3) ITI factor replacement regimen within the past one month unless there is clear evidence 
of ITI failure with no reduction in inhibitor titer over the past two months 
4) HIV positive with viral load ≥200 particles/µL or ≥400,000 copies/mL  
5) Rituximab within the past 3 months 
6) IVIG within the past 1 month 
7) Treatment with other immunosuppressive drugs within the past 1 month (excluding 
intermittent steroid use for asthma) 
8) Concomitant experimental treatment 
9) History of hypersensitivity to plasma-derived VWF- or FVIII-containing concentrates 
10) Elective surgery planned in the next 6 months (excluding vascular access procedure) 
11) Any condition or chronic illness, which in the opinion of the investigator makes 
participation ill-advised 
12) Inability or unwillingness to complete required screening, follow-up, and exit studies 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
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CRITERIA FOR EVALUATION: 
 
Efficacy: 
 
Primary Endpoint: 
The primary endpoint is time to inhibitor <0.6 BU.  
This endpoint was chosen because a shorter time to negative inhibitor should decrease monthly 
break-through bleeding frequency in the early phase of ITI, reduce morbidity and cost, and 
improve quality of life. 
Secondary Endpoints: 
Secondary endpoints include time to achieve partial and complete success as defined 
according to the following criteria:  
• 
Inhibitor titer <0.6 BU.  
• 
Incremental in vivo FVIII recovery in the normal range [≥66% of normal (1.5% per 
IU/kg), equal to 0.99%per IU/kg] with samples taken prior to and 15 or 30 minutes after 
concentrate treatment. The recovery assessment should be done without any wash-out 
period. 
• 
Half-life of FVIII >6 hours. The half-life assessment should be done in a non-bleeding 
status without any wash-out period. 
 
Complete Success (CS) of ITI: 
All three criteria above met. 
Partial Success (PS) of ITI: 
The first two of the three criteria above met. 
Partial Response (PR) of ITI: 
One of the three criteria above met. 
Partial Failure (PF) of ITI: 
Inhibitor still present, but titer is decreased to <5 BU in contrast to ≥5 BU before start.  
Complete Failure (CF) of ITI: 
None of the above mentioned criteria met, and the inhibitor titer is still ≥5 BU.  
 
 


  
 
 
 
 
 
 
 
 
 
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The following additional secondary endpoints will be evaluated: 
• 
Absence of relapse, up to 12 months after achievement of complete or partial ITI 
success 
• 
The number of break-through bleeding events during the course of ITI-treatment 
• 
Cost of ITI – including bleeding control using bypassing agents prior to start and during 
ITI 
• 
Health-Related Quality of life (HRQoL) 
• 
Adherence with the ITI treatment regimen 
• 
The impact of inhibitor titer at start of ITI and during the course of ITI, including the peak 
titer of the inhibitor 
• 
Additional biologic assays will be performed to understand factors related to ITI success. 
STUDY DESIGN: The INITIATE trial is a post-marketing investigator-initiated double-blinded 
randomized clinical study, comparing alternative therapy to standard therapy to reduce the time 
to inhibitor titer <0.6 BU. Participants from any Hemophilia Treatment Center in the US will be 
eligible. Each clinical site will be led by a hematologist experienced in the management of 
congenital hemophilia. 
STUDY POPULATION: Participants of any age with congenital hemophilia, FVIII activity ≤2% 
and historical high-inhibitor (≥5 BU).  
SAMPLE SIZE: 120 participants will be enrolled. 
RANDOMIZATION: Participants are randomized to treatment arm in a 2:1 ratio. A central 
laboratory will test each alternative treatment arm subject’s plasma sample against 4-6 factor 
lots and the lot with the lowest Oxford titer will be assigned. Subjects in the standard treatment 
arm will have lot assignment performed by random lot selection. The treating physician, 
treatment site staff, and participant will be blinded to the randomization allocation.  
DATA MANAGEMENT: Clinical sites enter data via a secure, internet-based electronic data 
capture (EDC) system. 
HUMAN SUBJECTS:  The most important risk for the participants is bleeding; high rates of 
bleeding are expected in individuals with Hemophilia A and inhibitors. 
 
 
 


  
 
 
 
 
 
 
 
 
 
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Table of Contents 
ABBREVIATIONS .......................................................................................................................................... 11 
Haemo-QoL 
The Quality of life assessment instrument for children and adolescents with 
haemophilia 
11 
DEFINITIONS ................................................................................................................................................ 13 
BACKGROUND AND SIGNIFICANCE ............................................................................................................. 14 
Inhibitor formation in patients with hemophilia .................................................................................... 14 
Management of high-titer inhibitors ...................................................................................................... 14 
STUDY OBJECTIVES AND PURPOSE ............................................................................................................. 20 
STUDY DESIGN ............................................................................................................................................ 21 
TREATMENT ARMS: ................................................................................................................................. 21 
Description of Primary and Secondary Endpoints .................................................................................. 22 
SELECTION OF PARTICIPANTS ..................................................................................................................... 23 
Enrollment Procedures ........................................................................................................................... 24 
TREATMENT OF PARTICIPANTS ................................................................................................................... 24 
High-Dose ITI Strategy............................................................................................................................. 24 
Drug Ordering, Storage, and Accountability ........................................................................................... 25 
Prior and Concomitant Therapy .............................................................................................................. 25 
Participant Adherence with ITI ............................................................................................................... 26 
Interruption of Study Drug ...................................................................................................................... 26 
Dose Reduction Based on Response to ITI .............................................................................................. 27 
Protocol-Directed Study Treatment Discontinuation ............................................................................. 27 
CLINICAL AND LABORATORY EVALUATIONS ............................................................................................... 27 
SCHEDULE OF EVENTS (See Appendix I) .................................................................................................. 29 
Evaluations at Eligibility Screening.......................................................................................................... 29 
Screening Evaluations ............................................................................................................................. 29 
Laboratory Evaluations during ITI Treatment ......................................................................................... 29 
Clinical Evaluations during ITI Treatment ............................................................................................... 30 
Laboratory Evaluations during Follow-Up .............................................................................................. 30 
Clinical Evaluations during Follow-Up ..................................................................................................... 30 
EFFICACY, SAFETY AND SPECIAL STUDIES ................................................................................................... 31 


  
 
 
 
 
 
 
 
 
 
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Efficacy .................................................................................................................................................... 31 
In vitro reactivity of FVIII inhibitors against lots of concentrate ............................................................ 31 
Safety ...................................................................................................................................................... 32 
Special Studies Performed at Central Labs (Optional) ............................................................................ 32 
Centralized Laboratory Measurements .................................................................................................. 32 
ITI Success Adjudication Process ............................................................................................................. 32 
Economic Impact Analysis ........................................................................................................................... 33 
Satisfaction/Health-Related Quality of Life ................................................................................................ 33 
INITIATE SAFETY MONITORING PROGRAM ................................................................................................ 33 
Adverse Events ........................................................................................................................................ 34 
Definitions ............................................................................................................................................... 34 
Adverse Event Reporting ........................................................................................................................ 35 
Severity of AEs ........................................................................................................................................ 35 
Causality of AEs ....................................................................................................................................... 35 
Classification of ADRs .............................................................................................................................. 36 
Outcome of AEs ...................................................................................................................................... 36 
Action(s) taken ........................................................................................................................................ 36 
Serious Adverse Events (SAEs) ................................................................................................................ 37 
SAE Reporting Timelines ......................................................................................................................... 37 
Other Relevant Safety Information ......................................................................................................... 38 
REGULATORY AND CLINICAL MONITORING ................................................................................................ 39 
DATA COLLECTION ...................................................................................................................................... 39 
Data Entry and Case Report Forms ......................................................................................................... 39 
STATISTICAL ANALYSIS ................................................................................................................................ 39 
HUMAN SUBJECTS PROTECTION ................................................................................................................. 40 
Risk to the Subjects ................................................................................................................................. 40 
Adequacy of Protection against Risks ..................................................................................................... 40 
Oversight of the Study ............................................................................................................................ 41 
Ethics ........................................................................................................................................................... 41 
GCP and IRB Review ................................................................................................................................ 41 
Informed Consent ................................................................................................................................... 42 


  
 
 
 
 
 
 
 
 
 
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Confidentiality ......................................................................................................................................... 42 
Disclosure of Data ................................................................................................................................... 42 
Publication of Research Findings ............................................................................................................ 42 
REFERENCES ................................................................................................................................................ 43 
Appendix I: Schedule of Events ................................................................................................................... 49 
Appendix II. Dosing Chart ............................................................................................................................ 51 
Appendix III: Subject Flow Diagram ............................................................................................................ 55 
Appendix IV: Dose Reduction for Participants on Hemlibra® .................................................................... 56 
 
 
 


  
 
 
 
 
 
 
 
 
 
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ABBREVIATIONS 
AE 
 
Adverse Event 
AHCDC  
Association of Hemophilia Clinic Directors of Canada 
APC 
 
Antigen Presenting Cell 
aPCC  
activated prothrombin complex concentrate 
ASH 
 
American Society of Hematology 
 
ASPHO 
American Society of Hematology/Oncology 
BU 
 
Bethesda Unit 
CF 
 
Complete Failure 
CR 
 
Complete Response 
CV 
 
Curriculum Vitae 
DSMC  
Data Safety Monitoring Committee 
EDC 
 
Electronic Data Capture 
eCRF  
Electronic Case Report Form 
FDA 
 
Food and Drug Administration 
FVIIa  
Activated Factor VII 
FVIII 
 
Factor VIII 
FWA  
Federal Wide Assurance 
GCP 
 
Good Clinical Practice 
Haem-A-QoL Haemophilia-specific Quality of Life Questionnaire for Adults 
Haemo-QoL 
The Quality of life assessment instrument for children and adolescents with 
haemophilia 
HRQoL 
Health-Related Quality of Life 
ICH 
 
International Committee on Harmonization 
ISTH  
International Society on Thrombosis and Haemostasis 
ITI 
 
Immune Tolerance Induction 
IU 
 
International Unit 
IVR 
 
In vivo recovery 


  
 
 
 
 
 
 
 
 
 
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kg 
 
Kilogram 
MASAC 
Medical & Scientific Advisory Council 
mL 
 
Milliliter 
NHF 
 
National Hemophilia Foundation 
OU 
 
Oxford Unit 
pd 
 
Plasma-derived 
PF 
 
Partial Failure 
PI 
 
Principal Investigator 
PR 
 
Partial Response 
PUPs  
Previously Untreated Patients 
rVIIa 
 
Recombinant activated factor VIIa 
rFVIII  
Recombinant factor VIII 
SAE 
 
Serious Adverse Event 
SC 
 
Study Coordinator 
SCC 
 
Study Coordinating Center 
TDH 
 
Terminal Dry-Heat 
UKHCDO 
UK Haemophilia Central Doctors Organization 
VWF  
Von Willebrand factor 
VWD  
Von Willebrand disease 
 
 


  
 
 
 
 
 
 
 
 
 
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DEFINITIONS 
 
Low responding inhibitor 
Inhibitor level is remains <5 BU/mL despite 
ongoing factor exposure. 
High responding inhibitor 
Inhibitor level is ≥5 BU/mL at any time 
Joint bleed 
Any complaint requiring treatment located in 
a joint 
Soft tissue bleed 
Any complaint requiring treatment located 
outside the joints 
Minor bleed 
Bleed characterized by mild pain, minimal 
swelling, minimal restriction of motion, 
resolving with 24 hours of treatment and not 
resulting in a life-threatening condition 
Major bleed 
Any bleed not considered minor 
Negative inhibitor 
A negative inhibitor is defined as a titer <0.6 
BU 
FVIII half-life 
Time (in hours) to 50% decrease in FVIII 
activity 
Inhibitor titer 
The inhibitor titer is the reciprocal of the 
dilution of subject plasma which results in 
50% of residual FVIII 
Normal in vivo FVIII recovery 
FVIII recovery ≥66% normal  
Bypassing agents 
Clotting factor concentrates used for the 
treatment or prevention of bleeding in 
hemophilia subjects with inhibitors. The 
action of the bypassing agent is 
independent of FVIII. 
Exposure day (ED) 
Any day during which factor therapy is 
given, regardless of the number of 
treatments in that day. 
 
 


  
 
 
 
 
 
 
 
 
 
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BACKGROUND AND SIGNIFICANCE 
Inhibitor formation in patients with hemophilia 
Anti-FVIII inhibitor (antibody) formation is the most serious complication of Hemophilia A 
treatment today, being estimated to occur in up to 10-30%, or more, of those with severe 
Hemophilia A. Use of FVIII is generally futile in this group, because the inhibitor will rapidly 
inactivate the infused concentrate.  
More than 90% of inhibitors occur within the first 50 exposure days and 50% before the first 15 
exposure days. Several risk factors for the development of inhibitors to FVIII have been 
identified in patients with Hemophilia A. The incidence of inhibitors depends on both,  
genetic factors: 
• 
severity of hemophilia 
• 
type of mutation1  
• 
ethnicity2 
• 
family history of inhibitors3 
• 
the HLA genotype4,5 
 
and non-genetic factors: 
• 
age at first FVIII treatment6,7 
• 
intensity of FVIII treatment8 
• 
continuous infusion of FVIII9 
• 
type of FVIII concentrate used10 
 
Walsh and colleagues from the Centers for Disease Control and Prevention recently 
demonstrated a higher rate of mortality in FVIII inhibitor patients.11 In multivariate analysis the 
odds of death were 70% higher among patients with a current inhibitor compared to those 
without an inhibitor (p<0.01), and the deaths among inhibitor patients were primarily attributed to 
bleeding complications. 
 
Management of high-titer inhibitors 
 
Management of Bleeding 
 
Treatment options for bleeding in patients with high-titer inhibitors include bypassing agents, 
activated recombinant coagulation factor VII (rFVIIa; NovoSeven®) and/or plasma-derived 
activated prothrombin complex concentrate (aPCC; FEIBA®), or porcine recombinant 
coagulation factor VIII (rFVIII; OBIZUR®). The efficacy of these agents is unpredictable and the 
results are suboptimal compared to direct FVIII replacement. 
 
 
 


  
 
 
 
 
 
 
 
 
 
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Prevention of Bleeding 
 
Ideally, patients with hemophilia should receive continuous, long-term prophylaxis to prevent 
spontaneous bleeding and hemophilic arthropathy. Inhibitors complicate the current standard of 
care, being three times weekly (or individualized) FVIII prophylaxis (preventive FVIII 
replacement therapy) to prevent joint bleeding and arthropathy long-term. Bypassing agents can 
be used for prophylaxis, but  must be given more frequently, are associated with high costs and 
are less efficacious compared to FVIII prophylaxis in patients without inhibitors. 
 
Immune Tolerance Induction  
 
ITI therapy is a program of regular infusions over a prolonged period of time to eradicate 
inhibitors. ITI is the treatment of choice to eliminate inhibitors and restore normal FVIII 
pharmacokinetics (recovery and half-life of FVIII). This enables regular FVIII treatment in the 
case of bleeding and surgery, as well as prophylactic treatment to prevent hemophilic 
arthropathy and life-threatening bleeding. Successful ITI leads to improved quality of life and 
reduced costs.12 
Current recommendations for ITI are based on data from ITI registries, systematic reviews 12-15 
and the International Immune Tolerance Study (NCT00212472).16 Several publications include 
guidance in terms of choice of product (VWF-containing plasma-derived (pd) FVIII).17-21 Expert 
groups in North America and Europe have published treatment experience and 
recommendations.22,23,24 The Association of Hemophilia Clinic Directors of Canada25 and UK 
Haemophilia Centre Doctors Organization)26 have published national clinical practice guidelines. 
The National Hemophilia Foundation (NHF) Medical & Scientific Advisory Council (MASAC) has 
not published clinical practice guidelines for the US.  
 
ITI Treatment Strategy 
 
The dose of FVIII used varies from 50 IU/kg on alternate days to 100 IU/kg twice daily. The 
International Immune Tolerance Study (NCT00212472) demonstrated a lower bleeding rate and 
shorter time to ITI success in participants treated with 200 IU/kg/day compared to 50 IU/kg three 
times per week.16 
Today rFVIII concentrates are the products of choice for standard Hemophilia A treatment in the 
US, also for 1st-line ITI treatment of inhibitors. Currently, no pdVWF/FVIII products are licensed 
specifically for ITI treatment by the Food and Drug Administration (FDA). Clinicians may choose 
to start with a pdVWF/FVIII product or switch to this product on an individual patient basis.22 
The REScue Immuntolerance Study (RESIST) (NCT01051544 and NCT01051076) aimed to 
compare ITI outcomes between rFVIII and pdVWF/FVIII ITI regimens.27 These studies were 
recently closed due to poor accrual. Data have not been published. The European PEDNET 
Hemophilia includes evaluation of etiology of inhibitors and ITI outcomes.28 The PRospectIve 
Observational Study of PlasMa-derived FVIII/VWF in Immune Tolerance Induction (PRISM) 
Registry is an observational study in the US evaluating inhibitor outcomes in patients treated 
with the pdVWF/FVIII concentrate, Alphanate®.29  
 
Duration of ITI 
 
ITI success is defined by a negative inhibitor titer (<0.6 BU), improved FVIII in vivo recovery 
(≥66 or 80% of calculated FVIII recovery) and increased FVIII half-life (≥6 or 7 hours).16,26,29  


  
 
 
 
 
 
 
 
 
 
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ITI may be achieved within 6-12 months, but can take as long as 1-3 (even more) years to 
achieve tolerance.30 Reported efficacy is 50-80% depending on the product used for ITI. 
Once tolerance is achieved, dose and frequency of factor infusions are gradually tapered to a 
prophylactic regimen.  Inhibitor titers and FVIII levels should be tested monthly during the first 
half year, subsequently every second month. After tolerance is achieved, it is recommended to 
follow the patients closely for relapses in order to restart ITI immediately.26 
Alternative strategies may be considered if the inhibitor titer fails to drop at least 20% over each 
6-months period after the peak titer has been reached.26 
Costs of Inhibitors and ITI 
 
Treating patients with high-titer inhibitors is costly.31 In addition to cost of FVIII during ITI, there 
are costs of bypassing agents to prevent and treat bleeding. ITI treatment is expensive in the 
short run. However, successful eradication of an inhibitor pays off in the long run. Once a 
negative inhibitor titer (<0.6 BU) is achieved the monthly bleeding rate drops by up to 90% 
(86.1-86.4% in the Octanate® study; data not published; Octanate® in ITI-BLA package 
submitted to FDA), and the use of bypassing agents and associated costs decrease. After 
successful ITI, prophylaxis is resumed. Overall, the cost of prophylaxis is three times less 
expensive than prophylaxis with bypassing agents32. Compared with patients on on-demand or 
prophylactic treatment using bypassing agents, subjects who have gone through a successful 
ITI have lower drug and hospitalization costs ($ 22.2 million vs. $ 38.7 million or $ 42.2 million), 
longer life expectancy (74.3 years vs. 69.6 years for both regimens), and fewer/almost equal 
bleeding events (801 vs. 1819 or 694), respectively.33  
The average direct medical costs for treatment of children and adults with inhibitors can be 
quantified in a cost of care analysis. Such an estimate has been done for Octanate® in ITI 
versus the on-demand use of NovoSeven®.34 The costs for on-demand pre-ITI phase 
management with NovoSeven® for one year was compared with the time period after start of 
high-dose ITI with Octanate®, and the break-even point analysis to estimate the number of 
years after which treatment with Octanate® pays off was done. The median age of initiation of 
high-dose ITI with Octanate® was 8 years for children and 23 years for adults. During the period 
with on-demand treatment of bleeding episodes with NovoSeven® before ITI with Octanate®, the 
children (n=8) had a mean body weight of 36 kg, bled 17 times per year, were treated for 6 days 
per bleed – twice per day – using 120 μg/kg, and were hospitalized 19 times per year. The ITI 
treatment was done with a mean of 230 IU/kg daily, bled 5 times per year, and were 
hospitalized zero times per year. The time until complete success was 11 months (range: 6-17) 
and the prophylactic dose after tolerance was 47 IU/kg three times per week. The treatment with 
high-dose ITI, including prophylaxis after tolerance, with Octanate® over 10 years had average 
costs of € 2.5 million, which is € 7.5 million less than the €10 million costs calculated for the on-
demand NovoSeven® option over 10 years. The mean break-even point was 1.2 years, after 
which ITI followed by prophylaxis with Octanate® was cheaper. For adults (n=8) the average 
cost saving was € 2.5 million and the break-even point was 3 years. 
Another break-even point calculation between ITI costs and the use of NovoSeven® on-demand 
in 10 high-responder children with inhibitors (mean age: 6 years) confirmed the above 
findings.35 The use of a bypassing agent might increase the costs of inhibitor treatment up to 12-
times over the patient’s lifetime, and the break-even point of ITI versus NovoSeven® on-demand 
was 1.4 years after treatment start.35  
Effect of VWF on ITI  


  
 
 
 
 
 
 
 
 
 
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The development of inhibitory antibodies to FVIII requires the interaction of antigen presenting 
cells (APCs), T-cells, and B-cells with the ability to recognize immunogenic peptides of FVIII.36 
VWF forms a non-covalently linked complex with FVIII to stabilize and protect it from protease 
degradation in the circulation.37 In addition, VWF may partially block the binding of immune cells 
to FVIII – especially the C2, A3, and maybe also A2 domains – and, thus, reduce the potential 
for inhibitor formation.37  
 
In vitro studies 
VWF reduces the immunogenicity of FVIII in Hemophilia A mice.38 Delignat et al hypothesize 
that VWF exerts at least two non-mutually exclusive immunoprotective roles towards FVIII – 1) 
VWF prevents (in a dose-dependent manner) the endocytosis of FVIII by professional APCs by 
blocking the interaction of FVIII with as yet unidentified endocytic receptor(s), a phenomenon 
also shown for human APCs;39 and 2) hypothetically, VWF, by virtue of increasing the half-life of 
FVIII in the circulation, may allow for an increased contact time with tolerogenic marginal B-cells 
in the spleen.38 
VWF-containing pdFVIII products protect FVIII better than nude FVIII against neutralizing 
antibodies in vitro,40 and that this causes a better recovery and half-life of FVIII in vivo.41 
Furthermore, pdVWF/FVIII concentrates added to FVIII-deficient plasma with the presence of an 
inhibitor generate more thrombin in vitro than nude FVIIIs – both plasma-derived and 
recombinant.42 Finally, it has been demonstrated – both in vitro and  by a tail clip survival test – 
that VWF has a dose-dependent protective effect on FVIII, limiting the inhibitor inactivation of 
FVIII, and that a preformed complex of VWF with FVIII provides more effective protection from 
inhibitors than a competitive binding of antibodies and VWF to FVIII.43 
Most recently, Bravo et al. studied the differential sensitivity to inhibitors of the native 
pdFVIII/VWF complex vs. the combination of purified, isolated FVIII and VWF proteins. They 
conducted in vitro inhibitor assays (BU) using various combinations of VWF and FVIII 
concentrates. Inhibitor titers were higher (i.e. residual FVIII lower) for all nude FVIII concentrates 
compared to plasma and pdFVIII/VWF concentrates despite pre-incubation with VWF. Thrombin 
generation was lower with nude FVIII concentrates compared to plasma and PDFVIII/VWF 
concentrates.44 Based on these findings, the authors recommend that Bethesda assay titration 
using different FVIII concentrates be used to select the optimal concentrate for ITI.44 This 
recommendation supports the INITIATE study design.  
 
Clinical Data of VWF/FVIII Concentrates for ITI 
 
Octapharma conducted a comparison of 26 studies comprising 511 patients undergoing ITI, of 
which 315 subjects participating in 13 studies received pdVWF/FVIII21,45-54 and 196 patients in 
another 13 studies received nude (recombinant) FVIII.55-67 The patient cohorts in all these 
publications were incompletely described, but there is a trend towards improved ITI results in 
patients who previously failed ITI in the pdVWF/FVIII trials than the rFVIII studies. It is clear from 
this comparison that both pdVWF/FVIII and rFVIII products are different in terms of the ITI 
success rates. The overall success rate (i.e. both complete and partial success) ranged from 
57.5% to 94.1% for the pdVWF/FVIII concentrates, with a complete success rate ranging from 
32.0% to 87.9%. When the still ongoing studies53,54 were excluded, the weighted average 
complete, partial, and overall success rates were 61.0%, 17.4%, and 78.4%, respectively. The 
two products Alphanate® and Fanhdi® (being essentially the same product, using the same 
manufacturing method) impacted the success rates significantly with a low complete success 


  
 
 
 
 
 
 
 
 
 
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rate of 43.8% and a high partial success rate of 30.8% (to a total of 74.7%), a difference which 
was statistically significant versus the other pdVWF/FVIII products (p<0.001). When these 
products were excluded from the analysis, the complete, partial, and overall success rates were 
improved to 76.7%, 5.0%, and 81.8%, respectively. The Octanate® figures were 70.8%, 8.3%, 
and 79.1%, respectively (total n=48), whereas the Wilate® studies are ongoing (see below ‘ITI 
treatment experience with Octanate® and Wilate®’). Haemoctin® from Biotest (identical to 
Octanate®) and Factane® from LFB (Octanate® without heat-treatment, but with nanofiltration) 
showed similar complete response rates to Octanate® with 64.3% and 87.5%, respectively. 
None of the success rates were dependent on the actual amount of VWF in the products. Thus, 
the differences seen are most likely related to the quality of VWF and how the FVIII is protected 
by VWF in the various pdVWF/FVIII concentrates. 
 
The rFVIII products had an overall success rate ranging from 25.0% to 81.8%, with a complete 
success rate in the range from 0.0% to 81.8%. The weighted average complete, partial and 
overall success rates were 57.1%, 9.2%, and 66.3%, respectively, which is not different from the 
pdVWF/FVIII except for more partial success in the pdVWF/FVIII group. Among the rFVIIIs, 
Kogenate®/Kogenate FS® had a complete response rate higher than Recombinate®/Advate® 
(68.1% vs. 43.2%; p<0.05). Alphanate® and Fanhdi® had fewer complete responses and more 
partial responses than the rFVIII concentrates – 43.8% vs. 57.1% and 30.8% vs. 9.2% (both p 
values <0.05), respectively. When these products were excluded from the pdVWF/FVIII 
products, the complete, partial, and overall success rates were improved to 76.7%, 5.0%, and 
81.8%, respectively, which revealed a significantly better performance for the pdVWF/FVIII 
concentrates over the rFVIIIs with 76.7% (+34.3%) vs. 57.1% for the complete responses and 
81.8% (+23.4%) vs. 66.3% for the overall responses (both p values <0.05; the partial response 
rate was not different). Based on all these studies it is reasonable to assume that the complete 
success rate in ITI is at least 45-75% for pdVWF/FVIII (excluding Alphanate® and Fanhdi®) 
versus 30-60% for rFVIII preparations, i.e. around 33% higher for pdVWF/FVIII. 
 
Individualized Selection of VWF/FVIII Lots for ITI 
 
Individualized selection involves measuring residual FVIII activity when patient plasma is mixed 
with VWF/FVIII concentrate in vitro. The lot of VWF/FVIII resulting in the highest residual FVIII 
activity is selected for use in ITI.  
 
Today, several methods, including the modified Oxford method, are used for measuring residual 
FVIII activity after incubation of a FVIII source (concentrate or plasma) with the inhibitor patient 
plasma.68 The inhibitor titer is the reciprocal of the dilution of patient plasma which results in 
50% of residual FVIII, and the difference between 1 Bethesda unit (BU) and 1 Oxford unit (OU) 
is 1 BU ≈ 1.21 OU – which equals 1 OU ≈ 0.83 BU. The relationship between the residual factor 
VIII values and BU or OU is described by the equations FVIIIres=e(-0.69)BU and FVIIIres=e(-0.83)OU. 
The principle of lot selection is to first test the inhibitor-containing plasma against a FVIII 
standard to establish the patient’s inhibitor titer (normal BU determination) and then to test 
several lots of a product against the same inhibitor plasma to find a lot which gives the highest 
residual FVIII content (lowest OU titer). Ideally, the lot providing the highest residual FVIII titer 
after infusion to the patient, i.e. after being subjected to the anti-FVIII, will challenge the immune 
system more and provide better prevention and control of bleeding. 
 
This strategy is being evaluated in the ObsITI study. ObsITI is an observational study of ITI in 
Europe (www.obsiti.com). The objective is to investigate the role of in vitro tests including lot 


  
 
 
 
 
 
 
 
 
 
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selection according to the modified Oxford method (described above) on individual ITI success 
rates in patients undergoing ITI. 
 
Data on the Role of Lot Selection in ObsITI 
Octanate® Data 
An analysis of 42 Octanate® ITI patients from ObsITI with complete details on the lots used was 
performed. Thirteen (31.0%) subjects used only selected lots, whereas 29 (69.0%) received 
random lots (i.e. could be either ideal or suboptimal lots used, details not known). Among the 
patients with selected lots 11 (84.6%) had a complete response, the remaining 2 (15.4%) had a 
partial response. There were no failures in this group. In the random lot cohort, 21 (72.4%) had 
a complete response and 3 (10.3%) had a partial response, whereas there were 5 (17.2%) 
failures in this group. None of these differences was significant statistically. Two of the patients 
had inhibitor titers above 200 BU, both of them were in the random group – 1 complete success 
and 1 failure. These were defined as outliers. Based on the time to reach a negative inhibitor 
titer (<0.6 BU; criteria 1), FVIII incremental recovery ≥80% (criteria 2), and FVIII half-life ≥7 
hours (criteria 3), Kaplan-Meier curves for the two cohorts were made, displaying the days 
versus the probability of reaching each of the three criteria. The time to reach a negative 
inhibitor titer (<0.6 BU; criteria 1) was shorter for the patients with lot selection, although the 
difference did not reach completely the significance level (p=0.061). The time to reach a FVIII 
incremental recover ≥80% (criteria 2) was again shorter for the subjects in the lot selection 
group and this difference was significant (p=0.013), whereas the time to reach a FVIII half-life ≥7 
hours (criteria 3) was the same for the two groups (p=0.78). The median time to reach a 
negative inhibitor titer (<0.6 BU; criteria 1) with a probability of 50% (0.5) was calculated to be 
49 days versus 132 days for the batch selection versus the random lot group, respectively. The 
median time to reach a FVIII incremental recovery ≥80% (criteria 2) with a probability of 50% 
(0.5) was of course slightly longer, but showed the same roughly three months difference with 
78 days versus 151 days for the lot selection versus the random lot group, respectively. The 
hazard risk ratios calculated were 5.3 and 2.85 for the time to criteria 1 and 2, respectively. With 
a hazard ratio of 2 (and outliers excluded) combined with e.g. a power of 85% and an alpha of 
2.5% or a power of 90% and an alpha of 5%, roughly 50 patients in each arm (100 in total) 
would be needed to show a difference between lot selection and random lots in ITI, using time 
until reaching a ‘negative inhibitor titer (<0.6 BU; criteria 1) with e.g. a ≥80% reduction in the 
monthly bleeding rate’ and/or reaching a ‘FVIII incremental recover ≥80% (criteria 2)’ as the 
end-point(s). To use ‘complete success’ (i.e. fulfilled criteria 3) as end-point is unrealistic, as 
there were no difference between lot selection and random lots in this analysis, although the 
reason for that can be that some of the random lot patients probably got ‘good lots’ too. 
 
Wilate® for Use in ITI 
 
Wilate® was launched for the first time in Germany in 2005, and is approved for the treatment of 
both von Willebrand disease (VWD) and Hemophilia A in Europe.69 In the US, Wilate® is 
approved only in VWD (since 2009).70 Wilate® is a high-purity (i.e. 100 IU FVIII/mg total protein) 
pdVWF/FVIII complex concentrate, purified by the use of ion-exchange chromatography 
columns, viral safeguarded by a combination of the chemical solvent/detergent (S/D) treatment 
(gold-standard for enveloped viruses such as HIV, HBV, and HCV) and terminal dry-heat (TDH) 
treatment (state-of-the-art method for both enveloped and non-enveloped viruses – the latter 
like HAV and parvovirus B19).71 Wilate® is further purified by size exclusion chromatography 
(SEC) and a special ultra-/dia-filtration (UF/DF) technique. Parvovirus B19 responds completely 
different to heat inactivation than other viruses. The externalization of the viral DNA, leaving an 
empty – but intact capsid, renders the virus non-infective – but still immunogenic.72 Thus, 


  
 
 
 
 
 
 
 
 
 
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seroconversion with formation of anti-B19 IgG is possible in recipients of heat treated 
pdVWF/FVIII concentrates, but disease is not transmissible at the conditions used, including a 
specified residual moisture.73 The TDH treatment of Wilate® is 2 hours during manufacturing.74  
Wilate® possesses all the important features asked for in ITI, namely high purity, a very high 
pathogen safety profile, and an excellent protection of its FVIII by VWF – all achieved through 
unique, novel, and innovative techniques such as: SEC and special UF/DF with a high cut-off, 
as well as an optimized lyophilization and full residual moisture testing combined with a 
prolonged TDH treatment. 
 
Octapharma has reserved lots of Wilate® for this trial. 
 
 
Wilate® Data 
From the ObsITI database there are two German patients who received Wilate® for ITI, both 
completed successfully. The two single cases represent one case each of 1st- and 3rd-line ITI. 
The number of poor prognosis factors was 3 and 4, respectively, including a historical peak titer 
of ≥200 BU. The 3rd-line ITI patient was switched to Wilate® only after 16.5 years, with the two 
previous attempts being done with a pdFVIII (almost devoid of VWF) and pdVWF/FVIII product 
other than Octanate® or Wilate® – with 2.4-fold more VWF than FVIII. The 1st-line ITI patient 
achieved a negative inhibitor after 2.8 months, normal FVIII recovery after 9.2 months, and a 
normal FVIII half-life after 10.2 months. The 3rd-line ITI achieved a negative inhibitor titer after 
3.3 years, normal FVIII recovery after 3.6 years and a normal FVIII half-life after 6.2 years.   
 
Two abstracts at the 2014 American Society of Hematology Annual meeting described ten 
Canadian patients who were prescribed Wilate® for ITI in Canada.53,54 Eight patients had 1 one 
or more poor prognostic factors. One patient (with 3 poor prognostic factors) has been defined 
as a failure, whereas the nine other subjects have achieved a reduction in the inhibitor titer and 
monthly bleeding rate,  including one complete success after four months.   
 
STUDY OBJECTIVES AND PURPOSE 
Rationale 
The rationale for this study is that an optimal regimen for ITI has not been defined, and patients 
with Hemophilia A and inhibitors have high morbidity, mortality, and associated costs. There are 
several ongoing registries to evaluate the etiology of inhibitors and to explore ITI outcomes, but 
there are no open ITI clinical trials at the current time. 
Primary and Secondary Objectives 
Primary Objective: The primary objective of the INITIATE trial is to compare individualized lot 
selection to random lot selection in time to negative inhibitor (<0.6 BU). 
 
Secondary Objectives: Secondary objectives of this study include the comparison of standard to 
alternative therapy for time to achieve partial and complete success, maintenance of inhibitor 
eradication, monthly break-through bleeding rates, cost of ITI – including bleeding control using 
bypassing agents prior to start and during ITI, quality of life, and adherence with ITI treatment 
regimen. Additionally, the impact of inhibitor titer at start of ITI and during the course of ITI, 


  
 
 
 
 
 
 
 
 
 
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including the peak titer of the inhibitor, will be investigated; and biologic assays will be done to 
understand factors related to ITI success. 
 
Hypothesis 
 
The primary hypothesis is that the time to negative inhibitor (<0.6 BU) will be shorter with 
individualized lot selection compared to random lot selection and that this will impact monthly 
break-through bleeding and reduce costs.  
STUDY DESIGN 
Description of Study Design 
 
The primary goal of the INITIATE trial is to compare the clinical outcome of individualized lot 
selection to random lot selection utilizing one plasma-derived VWF/FVIII complex concentrate 
for immune tolerance induction (ITI) in patients with congenital Hemophilia A, FVIII activity ≤2%, 
and a historical high-titer inhibitor (≥5 BU).  
 
The INITIATE trial is a post-marketing investigator-initiated double-blinded randomized clinical 
study comparing alternative therapy to standard therapy to reduce the time to partial or 
complete ITI success. Participants from any Hemophilia Treatment Center in the US will be 
eligible. Each clinical site will be led by a hematologist experienced in the management of 
congenital hemophilia. 
TREATMENT ARMS: 
Participants will be randomized on a two-to-one basis between one of two study arms, 
individualized lot selection (alternative treatment arm) and random lot selection 
(standard treatment arm, current US clinical practice in ITI). Study sites, participants, and 
investigators will be blinded to the treatment status assigned. 
 
Alternative treatment arm: 
Two-thirds of the participants will be randomized to blinded individualized lot selection for ITI. 
The target initial dose of FVIII for ITI is ~200 IU/kg/day intravenously, See Appendix II. The 
suggested maximum dose is 20,000 IU/day. Investigators may adjust the dose to a minimum 
dose of 150 units/kg if infusion volume is not feasible in patients without central venous access 
or in patients with von Willebrand factor levels >250%. Splitting dose into two infusions per day 
must be approved by the Steering Committee, and if approved, will be considered a protocol 
deviation. For subjects using Hemlibra®, the dose will be reduced to 50 IU/kg 3 times/week. 
Wilate® will be the VWF/FVIII complex concentrate (Octapharma USA, Inc., U.S. License No. 
1646) prescribed for ITI.  
 
Individualized lot selection will be performed according to a modified Oxford method in a central 
laboratory, by testing subject’s plasma against 4-6 lots of Wilate® and selecting the one with the 
highest residual FVIII (lowest Oxford titer) activity remaining after incubation. The same lot will 
be used throughout the entire ITI course for each subject. If the selected lot is depleted prior to 
the completion of ITI, a second individualized lot selection will be performed using the original 
plasma sample provided at baseline. 


  
 
 
 
 
 
 
 
 
 
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At six months, participants in the standard treatment arm who still have an inhibitor titer >0.6 
may be switched to the alternative treatment arm.They will be treated as new participants who 
have failed prior ITI and a second individualized lot selection will be performed using the original 
plasma sample provided at baseline. 
 
Each Wilate® batch includes 1.6-1.8 million IU and is expected to last for about 3-57 months 
depending on the weight of the subject and prescribed dose. See dosing chart. (Appendix II) 
 
Standard treatment arm:  
One-third of the participants will receive random lot selection for ITI. The dose and concentrate 
used will be the same. Concentrate will be randomly selected from available Wilate® lots. The 
same lot will be used throughout the entire ITI course for each subject. If the random lot is 
depleted prior to the completion of ITI, a second lot will be randomly selected. In both cases the 
random lot will be tested against subject’s plasma to measure the residual FVIII activity left after 
incubation but this result will not affect lot selection. 
 
Participants in the standard treatment arm will be offered the option of switching to the 
alternative treatment after 6 months if they have an inhibitor titer >0.6 BU. 
 
Description of Primary and Secondary Endpoints 
Efficacy 
 
Primary Endpoint: 
The primary endpoint is time to inhibitor <0.6 BU.  
 
Secondary Endpoints: 
Secondary endpoints include the time to achieve partial and complete success.  
 
The success of ITI is defined according to the following criteria: 
• 
Inhibitor titer <0.6 BU. 
• 
Incremental in vivo FVIII recovery in the normal range [≥66% of normal (1.5 %/IU/kg), 
equal to 0.99%/IU/kg] with samples taken prior to and 15 or 30 minutes after FVIII 
treatment. The recovery assessment should be done after the regular ITI treatment, 
without any wash-out period. 
• 
Half-life of FVIII >6 hours (blood samples for FVIII determination should be taken 6 + 2 
hours and 24 + 2 hours after FVIII treatment). The half-life assessment should be done 
in a non-bleeding status, e.g. after concentrate treatment, without any wash-out period 
interrupting the ITI. 
 
Complete Success of ITI: 
All three criteria above met. 
 


  
 
 
 
 
 
 
 
 
 
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Partial Success of ITI: 
The first two of the three criteria above met. 
Partial Response of ITI: 
One of the three criteria above met. 
Partial Failure of ITI: 
Inhibitor still present, but titer has decreased to <5 BU in contrast to ≥5 BU before start.  
Complete Failure of ITI: 
None of the above mentioned criteria met, and the inhibitor titer is still ≥5 BU.  
The following additional secondary endpoints will be evaluated: 
• 
Absence of relapse, up to 12 months after achievement of complete or partial ITI 
success 
• 
The number of break-through bleeding events during the course of ITI-treatment 
• 
Cost of ITI – including bleeding control using bypassing agents prior to start and during 
ITI 
• 
Quality of life 
• 
Adherence with the ITI treatment regimen 
• 
The impact of inhibitor titer at start of ITI and during the course of ITI, including the peak 
titer of the inhibitor 
• 
Additional biologic assays will be performed to understand factors related to ITI success. 
SELECTION OF PARTICIPANTS 
Inclusion Criteria: Subjects must meet all of the following criteria to be eligible for enrollment into 
the study: 
1) Diagnosis of congenital Hemophilia A and baseline FVIII ≤2%. 
2) Weight ≥ 5 kg 
3) History of FVIII inhibitor titer ≥5 BU 
4) Current FVIII inhibitor titer ≥5 BU or  ≥0.6 BU and failed ITI defined by FVIII recovery 
<66% normal and half-life <6 hours 
5) Adequate venous access for daily concentrate infusions 
6) For participants <18 years, a parent or guardian willing and able to provide informed 
consent with verbal or written assent from the child if require by the local institution. For 
participants ≥18 years, a willingness and ability to provide informed consent from the 
subject. 
7) Ability to comply with study related treatments, evaluations, and follow-up. 
 
Exclusion Criteria: Subjects meeting any of the following criteria are ineligible for enrollment in 
the study: 
1) Acquired hemophilia 
2) Congenital or acquired bleeding disorder in addition to Hemophilia A 


  
 
 
 
 
 
 
 
 
 
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3) ITI factor replacement regimen within the past one month unless there is clear evidence 
of ITI failure with no reduction in inhibitor titer over the past two months 
4) HIV positive with viral load ≥200 particles/µL or ≥400,000 copies/mL  
5) Rituximab within the past 3 months 
6) IVIG within the past 1 month 
7) Treatment with other immunosuppressive drugs within the past 1 month (excluding 
intermittent steroid use for asthma) 
8) Concomitant experimental treatment 
9) History of hypersensitivity to plasma-derived VWF- or FVIII-containing concentrates 
10) Elective surgery planned in the next 6 months (excluding vascular access procedure) 
11) Any condition or chronic illness, which in the opinion of the investigator makes 
participation ill-advised 
12) Inability or unwillingness to complete required screening, follow-up, and exit studies 
 
Enrollment Procedures 
Clinical sites will enroll research participants according to their institutional practices. Verification 
of eligibility will be conducted. The completed eligibility checklist and signed informed consent 
documents should be available as source documents for study monitor review. 
The eligibility screening period can only begin after the informed consent is obtained.  
TREATMENT OF PARTICIPANTS 
High-Dose ITI Strategy 
 
High-dose ITI strategy will be used for this study. Participants will be prescribed 200 IU/kg 
infused intravenously once daily. Doses will be rounded up to nearest 1000 units. See Appendix 
II for dosing chart. For subjects using Hemlibra®, the dose will be reduced to 50 IU/kg 3 
times/week. Treatment will be prescribed for a minimum of six months. 
Randomization 
 
Participants are randomized to either the Standard or Alternative Treatment Arm at a 2:1 ratio.  
 
Upon confirmation of eligibility, participants will be randomized by the Clinical Coordinating 
Center to maintain blinding of the site to randomization assignment. Randomization envelopes 
will be used. Based on randomization, lot assignments will be provided by the Clinical 
Coordinating Center to the sites. 
Randomization will occur approximately 1 month prior to treatment initiation to allow for lot 
selection and distribution of the assigned lot. 
 
Treatment Concentrate 
 
Standard Treatment Arm 
Wilate® will be the concentrate used for ITI in the Standard Treatment Arm. Concentrate from 
the randomly selected lot will be provided. 
 


  
 
 
 
 
 
 
 
 
 
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Alternative Treatment Arm 
Wilate® will be the concentrate used for ITI in the Alternative Treatment Arm. Concentrate from 
the individually selected lot will be provided. 
 
Packaging and Labeling of Factor Concentrate 
 
Wilate® is available as 500 and 1000 IU VWF/FVIII (ratio 1:1) vials. The vials are distributed with 
a Mix2Vial™ needle-free transfer device. 
 
Drug Ordering, Storage, and Accountability 
 
Drug Distribution 
Once subjects have enrolled, been randomized to receive a matched or random lot of product, 
the information as to which product lot has been assigned to that subject, using the subject’s 
identifying code, will be transmitted to ASD Healthcare. The subject’s treating institution will 
order product from ASD Healthcare through its usual distribution pharmacy using the subject’s 
identifying code in the same manner as any other patient product would be ordered. ASD 
Healthcare has committed to provide factor at or below what the institution would be charged if 
product were ordered for a non-study patient. ASD Healthcare will ship product to the pharmacy 
routinely used by the institution for that subject and product will be delivered to the subject in the 
usual manner for that pharmacy. 
Wilate® will be stored at the participant’s home either in the myCubixx refrigerator or their own 
refrigerator. The myCubixx refrigerator is also provided by ASD Healthcare.  
 
Prior and Concomitant Therapy 
 
Prior Therapy 
Prior ITI regimens are allowed. Prior ITI regimen must have been discontinued within 1 month of 
study enrollment unless there is clear evidence of ITI failure with no reduction in inhibitor titer 
over the past 2 months. 
 
Bypassing Agents 
As long as the subject’s inhibitor level is ≥0.6 BU, we expect that prevention and treatment of 
bleeding episodes may require bypassing agents.  
 
Prophylactic Therapy with Bypassing Agents (anti-inhibitor coagulant complex [FEIBA®],rVIIa, 
[NovoSeven®RT], and Hemlibra®) 
Bypassing agents mnay be prescribed as prophylaxis according to the participant’s bleeding 
tendency based on prior reports. The use of bypassing agents should be stopped once the 
subjects’ inhibitor level is <0.6 BU, but continued use is at the discretion of the treating 
physician. 
 
Bleed Treatment with Bypassing Agents (anti-inhibitor coagulant complex [FEIBA®] and rVIIa, 
[NovoSeven®RT]) 
 


  
 
 
 
 
 
 
 
 
 
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As guidance, the following treatment regimens might be used for treatment of hemorrhages or in 
subjects with a high bleeding tendency for prevention of bleeding 1,75   FEIBA®: 75-100 IU/kg, 
twice daily, dosage depending on severity of hemorrhage. Same dosage recommendation is 
given for prophylactic treatment in subjects with a high bleeding tendency. 
1) NovoSeven®RT)=: 90 µg/kg every 2 hours, dosage and frequency may be adjusted 
based on physician discretion depending on severity of hemorrhage. 
2) In case of insufficient effect with FEIBA® and/or NovoSeven®RT, recombinant porcine 
FVIII (rpFVIII,OBIZUR®) might be an alternative bleeding treatment: 50-100 IU/kg up to 
twice daily, dosage depending on severity of hemorrhage (only recommended in 
subjects with porcine FVIII inhibitor levels <20 BU). OBIZUR® is not approved by the 
FDA for the treatment of congenital Hemophilia A. 
Prophylactic Therapy with Non-factor replacement (emicizumab-kxwh, Hemlibra®)  
Hemlibra® is now FDA approved to prevent bleeding in patients with hemophilia A and FVIII 
inhibitors. There are no reports of use in combination with ITI and safety is unproven. If an 
investigator elects to use Hemlibra® along with ITI in patients with significant and frequent 
breakthrough bleeds then the dose of ITI should be reduced to 50 units/kg three times weekly. 
Investigators should follow prescribing information for Hemlibra® in regards to treatment of 
bleeding episodes with other Bypassing Agents (anti-inhibitor coagulant complex [FEIBA®] and 
rVIIa, [NovoSeven®RT]). 
Immunosuppression 
Immunosuppressant and immune modulating agents are not allowed with the exception of 
intermittent steroid use for asthma. 
 
Participant Adherence with ITI 
Adherence during ITI is very important, as interruptions of regular injections have the potential 
to reduce the chance for ITI success. Through a system like myCubixx from ASD Healthcare, 
with RFID-tagged product in a refrigerator with an RFID reader, information on whether subjects 
are following the treatment regimen can be accessed via a portal. In addition, the product on 
stock at each participant’s residence is monitored constantly, which allows for notification of the 
product stocks in real time. Smart tags in the myCubixx refrigerators use a secure cellular 
network, so no extra network or installation costs are needed. All information in the myCubixx 
portal is de-identified and do not contain Protected Health Information. 
 
In addition, sites will be performing drug accountability. Participants will be asked to bring their 
empty vials and boxes to their follow-up visits. 
Interruption of Study Drug 
ITI should not be interrupted for any reason, specifically not for recovery or pharmacokinetic 
assessments. If a participant is admitted the hospital, the assigned Wilate® lot should be utilized 
whenever possible. No more than 7 consecutive days of alternative concentrate will be allowed.  
 


  
 
 
 
 
 
 
 
 
 
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Dose Reduction Based on Response to ITI (See Appendix III for the Subject Flow 
Diagram)  
In cases where complete success is achieved, ITI will be terminated. The participant may start 
decreasing the ITI dose to eventually receive a prophylactic treatment regimen of ≤50 IU 
FVIII/kg every second day after complete inhibitor elimination as determined by his treating 
physician.  
In cases where partial success is achieved, ITI may be terminated or continued at discretion of 
the treating physician. 
In cases where partial response is achieved, ITI will be continued. 
Protocol-Directed Study Treatment Discontinuation 
Participants may decide to discontinue participation at any time during the study by withdrawing 
consent. Investigators may discontinue protocol-directed study treatment for any subject, if in 
their professional opinion, the subject’s health, safety, and/or well-being is threatened by 
continued protocol-directed study treatment. The following circumstances require 
discontinuation of protocol-directed study treatment: 
• 
ITI will be suspended in case of insufficient subject's adherence (<80% prescribed doses 
in a 3-month period or a single interruption in treatment of ≥7 days). The choice of 
further therapeutic options remains the responsibility of treating physician. 
• 
In cases of partial or complete treatment failure after a maximum study treatment period 
of 18 months, ITI will be terminated. The choice of further therapeutic options is the 
responsibility of the treating physician. At six months, participants in the standard 
treatment arm who still have an inhibitor titer >0.6 may be switched to the alternative 
treatment arm. 
CLINICAL AND LABORATORY EVALUATIONS 
The following clinical information will be collected during the screening period: 
 
a) Hemophilia type 
b) Hemophilia severity 
c) Baseline FVIII activity 
d) Medical co-morbidities 
e) Date of birth 
f) Race/ethnicity 
g) FVIII mutation (if known) 
h) Date inhibitor ≥0.6 BU first detected 
i) Inhibitor titer when first detected 
j) Date of peak inhibitor titer prior to any ITI 
k) Peak inhibitor titer prior to any ITI 
l) Prior ITI courses: 


  
 
 
 
 
 
 
 
 
 
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• 
Titer at start 
• 
Peak titer 
• 
Product used 
• 
Dose 
• 
Outcome 
m) Prior immunosuppressant or immune modulatory agents used for ITI 
n) Prior bypassing agents (type and frequency) 
o) In vitro reactivity of FVIII inhibitors against lots of concentrate 
 
 
Efficacy Studies and Assessments 
 
The following efficacy studies will be performed during the study: 
• 
FVIII inhibitor assay 
• 
FVIII recovery 
• 
FVIII half-life 
• 
Bleeding history 
Safety Assessments 
 
The following safety assessments will be performed during the study: 
• 
Hemophilia-related events 
• 
ITI-related AEs and SAEs 
o Infections 
o Thrombotic events 
 
Special Studies 
Several laboratory studies on participant blood samples will be performed in centralized 
laboratories as part of the secondary endpoint analyses. Samples will be collected for special 
laboratory studies, which will include the following: 
• 
Epitope mapping 
• 
Immunogenotyping/HLA genotyping 
• 
FVIII genetic testing 
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SCHEDULE OF EVENTS (See Appendix I) 
Evaluations at Eligibility Screening 
Prior to performance of any study-related procedures, subjects and/or their legally authorized 
representative must sign the informed consent document and minor subjects may be required to 
give assent as determined by the IRB of Record for the site. The subject will then be screened 
for eligibility prior to randomization. The eligibility screen period includes the analysis of the 
subject’s plasma in the central lab and must be completed in no more than 5 weeks. 
Screening Evaluations 
• 
Medical history/co-morbidities 
• 
Prior/concomitant medications 
• 
Weight and height 
• 
HRQoL assessment 
• 
Diary distribution 
• 
FVIII activity 
• 
FVIII inhibitor 
• 
VWF antigen/activity 
• 
Epitope mapping 
• 
Immunogenotyping/HLA genotyping 
• 
FVIII genetic testing  
• 
FVIII reactivity to Wilate® lots* 
 
*Three (3) tubes of blood will be collected and sent to the central lab. One (1) tube will be used for initial 
FVIII reactivity to Wilate® lot/s. The second and third tubes will be processed and stored. The additional 
tubes are to be used in the event that a lot is depleted by a subject and/or participants in the standard 
treatment arm who still have an inhibitor titer >0.6 are switched to the alternative treatment arm. A tube 
will be tested against Wilate® lot/s so a new lot can be assigned to the subject in both circumstances. If 
any of the additional tubes is not used during the subject’s participation in the study, the sample will be 
destroyed. 
Laboratory Evaluations during ITI Treatment 
The following tests will be done at 2 and 4 weeks after ITI initiation and then on a monthly basis: 
 
• 
FVIII inhibitor titer; if a negative result is obtained, a repeat test should be drawn within 1 
week 
 


  
 
 
 
 
 
 
 
 
 
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The following tests will be done at 2 and 4 weeks after ITI initiation and then on a monthly basis 
through week 24: 
 
• 
VWF activity and antigen 
 
The following tests will be done based on response to ITI: 
 
• 
FVIII assay 
• 
FVIII recovery (once FVIII inhibitor negative) 
• 
FVIII half-life  (once FVIII recovery at ≥66%) 
 
Laboratory tests will be collected at the research site.  
 
 
Clinical Evaluations during ITI Treatment 
Participants will have evaluations on a monthly basis until ITI is completed. Evaluations must be 
performed at the clinical site at least every 8 weeks. Clinical evaluations will be performed by 
telephone call 4 weeks after every in-person visit performed at the clinical site.  
 
The following information will be collected: 
 
• 
Concomitant medications 
• 
Changes to medical history/co-morbidities 
• 
Bleeding history 
• 
HRQoL (at first clinical evaluation after negative titer documented) 
• 
ITI-related AEs and SAEs 
• 
Height/weight (as indicated in the schedule of events) 
• 
Diary information  
 
Laboratory Evaluations during Follow-Up 
Laboratory tests will be done on an every-other month basis after complete or partial success. 
 
The following tests will be done: 
 
• 
FVIII inhibitor titer 
 
Clinical Evaluations during Follow-Up 
Participants will have evaluations at the clinical site every 8 weeks until week 52 after complete 
or partial success.  
 
The following information will be collected: 
 
• 
Concomitant medications 
• 
Changes to medical history/co-morbidities 
• 
Bleeding history 


  
 
 
 
 
 
 
 
 
 
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• 
HRQoL (study exit) 
• 
ITI-related AEs and SAEs 
EFFICACY, SAFETY AND SPECIAL STUDIES 
Protocol studies will be performed at central laboratories. Investigators desiring rapid laboratory 
results may perform studies in their local lab but official results to be used in data analysis will 
be from the central laboratory. 
Efficacy 
• 
FVIII inhibitor assay (performed at central lab) 
• 
FVIII activity assay (performed at central lab) 
 
• 
Incremental in vivo FVIII recovery in the normal range [≥66% of normal (1.5 %/IU/kg), 
equal to 0.99%/IU/kg] with samples taken prior to and 15 or 30 minutes after FVIII 
treatment. The recovery assessment should be done after the regular ITI treatment, 
without any wash-out period. 
• 
Half-life of FVIII >6 hours (blood samples for FVIII determination should be taken 6 + 2 
hours and 24 + 2 hours after FVIII treatment). The half-life assessment should be done 
in a non-bleeding status, e.g. after concentrate treatment, without any wash-out period 
interrupting the ITI. 
 
In vitro reactivity of FVIII inhibitors against lots of concentrate 
Alternative Treatment Arm 
For participants in the alternative treatment arm, the in vitro reactivity of FVIII inhibitors will be 
tested against the lots of the study concentrate. The test will be performed according to a 
modified Oxford method. The batch yielding the highest remaining FVIII activity and the lowest 
remaining inhibitor titer will be documented. A plasma sample will be retained in case that the 
first lot is depleted and another batch needs to be identified. 
At least three weeks prior to when a participant depletes his lot, a subsequent lot will be 
selected (randomly for the Standard Arm and based on FVIII reactivity to Wilate® lots for the 
Alternative Arm). 
Standard Treatment Arm 
For participants in the standard treatment arm, the in vitro reactivity of FVIII inhibitors against 
the randomly selected concentrate batch will be performed according to a modified Oxford 
method. This information will be used for secondary analyses.  A plasma sample will be retained 
in case that the first lot is depleted and another batch needs to be identified. 


  
 
 
 
 
 
 
 
 
 
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For both arms of the study, the lot/s of study concentrate against which subject plasma samples 
are tested are randomly chosen by the Coordinating Center from a database containing all lots 
currently available. Once a lot is assigned to the subject, verification of receipt of correct lot by 
the subject will be performed by the Coordinating Center through the myCubixx system. Any 
errors in lot distribution will be escalated and handled appropriately following standard 
procedures.  
Safety 
VWF activity and antigen will be performed at baseline and at interval study visits to determine if 
there is VWF accumulation during ITI. The rationale is that, although rare, significant thrombotic 
events have been reported during ITI with VWF/FVIII concentrate.76 
Special Studies Performed at Central Labs (Optional) 
Epitope Mapping 
The antibody epitopes on FVIII will be identified by screening peptide libraries and FVIII 
fragments with inhibitor patient plasma. This will help to identify relevant epitopes recognized by 
inhibitors in hemophilia A. This research program will give an opportunity to comprehensively 
study various aspects of inhibitors and the induction of immune tolerance in a relevant number 
of patients. Knowledge about relevant epitopes from patient plasma rather than from model 
systems (i.e. monoclonal antibodies or mouse models) will help to understand the immune 
response to FVIII and to develop novel strategies to deplete inhibitors or inhibitor secreting B 
cells (University Hospital Frankfurt, Laboratory for Molecular Haemostasis and 
Immunodeficiencies, Frankfurt, Germany). Results will not be shared with the site investigators. 
Immunogenotyping/HLA genotyping 
This study will investigate genetic risk factors (gene defect responsible for hemophilia, HLA 
class II alleles, and immune response genes) as a potential variable with impact on course and 
outcome of ITI. Recently a significantly higher inhibitor incidence has been found in patients 
(brothers) with IL-10.G allele 134, TNFA - 308G>A polymorphism within Hap and 
polymorphisms in the CTLA-4-gene compared to those brothers without the above mentioned 
polymorphisms77-79 (University Hospital Bonn, Haemophilia Centre, Bonn, Germany). These 
tests are desired but not mandatory. Results will not be shared with the site investigators. 
 
Factor VIII genetic testing  
Genetic testing to identify the causative FVIII mutation will be done in conjunction with the HLA 
genotyping. This test is desired but not mandatory. Results will be shared with the site 
investigators. 
Centralized Laboratory Measurements 
Specimens sent to the Central Lab are identified by a specimen ID number, and the Central Lab 
will remain masked to subject ID and treatment assignment. 
 
ITI Success Adjudication Process 
INITIATE will employ a masked process for determining ITI success. The INITIATE Steering 
Committee will review all of the primary efficacy data to determine ITI success. 


  
 
 
 
 
 
 
 
 
 
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Economic Impact Analysis 
It is expected that participants who achieve criterion 1 (loss of a measurable inhibitor titer) will 
have a dramatic decrease in the rate of bleeding and the need for and use of bypassing agents. 
This should have an impact on the cost of therapy. The use of all clotting products will be 
assessed in all study participants. The use of the myCubixx system should improve the 
collection of the data as to the number of times factor is used, the date of use, and the type of 
factor and for what purpose. This will allow calculation of the average number of doses of 
product used for prophylaxis, for bleeding episodes and the number of units. Average 
costs/bleeding episode can be calculated as well as total costs over time. The costs will be 
estimated from the average sales price of each factor product as published by the Centers for 
Medicare and Medicaid Services (CMS) on the CMS.gov website. This information can be 
divided by cost early during ITI, cost after reaching criteria 1 and 2. All costs will be calculated in 
US dollars and average sales prices can be determined by year of use since the CMS data is 
updated annually. 
Satisfaction/Health-Related Quality of Life 
The loss of an inhibitor with the concomitant reduction in bleeding episodes, decrease in use of 
bypassing agents and eventual reduced frequency of dosing of factor VIII should be 
accompanied by an improved health-related quality of life (HRQoL). HRQoL will be assessed 
with hemophilia-specific HRQoL questionnaires according to different age groups, which have 
been linguistically validated and culturally adapted for the respective languages83.  
• 
The ‘Quality of life assessment instrument for children and adolescents with 
haemophilia’ (Haemo-QoL) will be used to assess HRQoL for children and adolescents84 
. It consist of 21-77 items depending on the age group pertaining to 8-13 domains, 
respectively and a total score with high values implying high impairments in HRQoL.   
• 
The ‘Haemophilia-specific Quality of Life Questionnaire for Adults’ (Haem-A-QoL)85  will 
be used to assess HRQoL in adults. It consists of 46 items pertaining to 10 domains and 
a total score. High values imply high impairments in HRQoL.  
Assessments will be performed at the start of the study, at the first clinical evaluation after 
negative titer documented, and at study exit. Raw data will be normalized for each study and 
summary statistics generated for study participants at each time point as well as longitudinally 
per participant. 
INITIATE SAFETY MONITORING PROGRAM 
Safety Assessment 
Hemophilia-Related Events 
A variety of adverse events (AEs) and some serious adverse events (SAEs) are expected to 
occur during the INITIATE trial due to the nature of the underlying disease and the clinical status 


  
 
 
 
 
 
 
 
 
 
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of the enrolled subjects. These AE/SAEs will not necessitate discontinuation of treatment and 
withdrawal from the study.  
ITI-Related Complications 
• 
Infections 
• 
Thrombotic Events 
Safety Monitoring Program 
 
Safety monitoring will include data capture for adverse events and adverse reactions, safety 
reviews, and reporting.  
Data Capture 
 
Clinical data will be captured for subject-reported adverse event or suspected adverse reaction 
information at the time of a study visit. SAEs must be reported in an expedited fashion. 
A Data Safety Monitoring Committee (DSMC) will review the reported adverse events.  
After reviewing the safety event, the DSMC may recommend a modification of the protocol, 
termination of the project for an individual center or participant or propose interim analyses. 
Any of the following drug safety information shall be collected: 
– 
Adverse events (AEs) and serious adverse events (SAEs) temporally associated 
with the administration of Wilate® (definitions and reporting requirements see below) 
– 
Other relevant safety information, including post-study safety reports, instances of 
drug overdose, drug-drug interactions, abuse, misuse, medication error, or lack of 
efficacy (see below) 
 
Adverse Events 
Definitions 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Council on 
Harmonisation [ICH])  
 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.  
 


  
 
 
 
 
 
 
 
 
 
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Note: The sponsor collects AEs starting with the signing of the ICF. 
Adverse Event Reporting 
The condition of the subject will be monitored throughout the study. At each scheduled or 
unscheduled study visit, AEs will be elicited using a standard non-leading question such as 
“How have you been since the last visit?” In addition, the subject diaries will be checked by 
study personnel for any documented event. 
Any AE or ADR which occurs during the study will be documented in detail on the appropriate 
CRF. If the subject reports several signs or symptoms representing a single syndrome or 
diagnosis, the syndrome or diagnosis should be recorded in the CRF. The investigator 
responsible will grade the severity of all AEs or ADRs (mild, moderate, or severe), the 
seriousness (non-serious or serious), and the causality as defined below. The Sponsor is 
responsible for assessing the expectedness of each ADR (expected or unexpected) as defined 
below. 
In the event of clinically significant abnormal laboratory findings, the tests will be repeated and 
the subject followed up until the laboratory values have returned to normal and/or an adequate 
explanation for the abnormality has become available. 
Diseases, signs, and symptoms and/or laboratory abnormalities already present before the first 
administration of medicinal product will not be considered AEs unless an exacerbation in 
intensity or frequency (worsening) occurs. 
The responsible investigator will provide detailed information about any abnormalities and about 
the nature of and reasons for any action taken as well as any observations or comments that 
may be useful for the interpretation and understanding of an AEs or ADR. 
Severity of AEs 
The severity of AEs will be graded as follows: 
• 
  Mild: an AE, usually transient, which causes discomfort but does not interfere with the 
subject’s routine activities 
• 
  Moderate: an AE which is sufficiently discomforting to interfere with the subject’s 
routine activities 
• 
  Severe: an AE which is incapacitating and prevents the pursuit of the subject’s routine 
activities. 
• 
 
The grading of AEs is up to the medical judgment of the investigator and will be decided on a 
case-by-case basis. 
Causality of AEs 
The relationship of AEs to the administered medicinal product will be assessed by the 
responsible investigator. The causality of AEs will be classified as follows:  
• 
Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from 


  
 
 
 
 
 
 
 
 
 
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administration of the medicinal product; or that follows a known or expected response 
pattern to the suspected medicine; or that is confirmed by stopping or reducing the 
dosage of the medicine and that could not reasonably be explained by known 
characteristics of the subject’s clinical state. 
• 
Possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection is 
uncertain or doubtful, for example because of missing data or insufficient evidence. A 
reaction that follows a reasonable temporal sequence from administration of the 
medicinal product; that follows a known or expected response pattern to the suspected 
medicine; but that could readily have been produced by a number of other factors. 
• 
Unlikely: reports not following a reasonable temporal sequence from medicinal product 
administration. An event which may have been produced by the subject’s clinical state or 
by environmental factors or other therapies administered. 
• 
Not related (unrelated): events for which sufficient information exists to conclude that 
the aetiology is unrelated to the medicinal product. 
• 
Unclassified: reports which for one reason or another are not yet assessable, e.g. 
because of outstanding information (can only be a temporary assessment). 
Classification of ADRs 
ADRs will be classified as expected or unexpected: 
• 
Expected: an AE that is listed in the Wilate® package insert. 
• 
Unexpected: an AE that is not listed in the Wilate® package insert, or that differs 
because of greater severity or greater specificity. 
Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
(a) Recovered, resolved 
(b) Recovering, resolving 
(c) Not recovered, not resolved 
(d) Recovered, resolved with sequelae 
(e) Fatal 
(f) Unknown 
A subject’s death per se is not an event, but an outcome. The event having resulted in the 
subject’s death must be fully documented and reported. Deaths occurring within 4 weeks after 
medicinal product (Wilate®) treatment end also have to be reported, regardless of whether or 
not they are considered treatment-related. 
Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of medical care to 
safeguard the health and well-being of the subject. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment of an emergency situation. 
The action taken by the investigator must be documented: 


  
 
 
 
 
 
 
 
 
 
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• 
General actions taken in the event of an AE 
o None 
o Medication (other than Wilate®) or other (e.g., physical) therapy started 
o Test performed 
o Other (to be specified) 
The responsible investigator will follow up on each AE until it has resolved or until the medical 
condition of the subject has stabilized. Any relevant follow-up information will be reported to the 
Sponsor. 
Serious Adverse Events (SAEs) 
 
Serious Adverse Event  
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:  
• 
Results in death  
• 
Is life-threatening (The subject was at risk of death at the time of the event. It does not 
refer to an event that hypothetically might have caused death if it were more severe.)  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is Medically Important* 
 
* Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as, important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious. 
 
One such ‘important medical event’ is the suspected transmission of an infectious agent. 
These events, therefore, have to be reported as SAEs. 
A suspected virus transmission means that virus antigen has been detected in the subject. The 
passive transmission of antibodies alone does not constitute a suspected virus transmission. 
SAE Reporting Timelines 
 
Within 24 hours after recognition of the event, a ‘Serious Adverse Event Report’ must be 
completed and submitted whether or not they are suspected to be related to the study 
treatment. All SAEs should be reported to the Coordinating Center.  
Exemption from the SAE reporting requirement 
Exemptions from the SAE reporting requirement include surgeries that are elective or had been 
planned before study entry or prolongations of existing hospitalizations for economic or social 


  
 
 
 
 
 
 
 
 
 
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rather than medical reasons. Such surgeries or prolongations of hospitalizations should not be 
considered SAEs. 
Other Relevant Safety Information 
Instances of drug overdose, drug-drug interactions, abuse, misuse, medication error, or lack of 
efficacy (items (b) to (g)) should be reported as AEs or SAEs, as applicable. 
(a) Post-study safety reports 
The investigator should also report any ADR (i.e., any AE with a suspected causal relationship 
to the medicinal product) occurring after completion of the study. The usual procedure for 
reporting post-marketing safety information should be followed, but the suspected causal 
relationship to the clinical study should be stated on the report. 
(b) Drug overdose 
An overdose is the deliberate or inadvertent administration of a treatment at a dose higher than 
that specified in the protocol and higher than the known therapeutic dose, and it must be of 
clinical relevance. The event must be clearly identified as an overdose. 
(c) Drug-drug interactions 
A drug interaction is a situation where a substance/medicinal product affects the activity of a 
medicinal product, i.e. increases or decreases the effect(s) of an medicinal product, or produces 
an effect that none of the products would exhibit on their own. The event must be clearly 
identified as resulting from a drug-drug interaction. 
(d) Abuse 
Abuse is the deliberate use of a medicinal product that may lead to addiction accompanied by 
harmful physical or psychological effects. 
(e) Misuse 
Misuse is the deliberate administration or use of the medicinal product outside its described 
indication or outside the current state of the art medical practice (off-label-use). The reaction 
must be clearly identified as misuse. 
(f) Medication error 
Medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical form/packaging, 
instructions for use/labelling. The reaction must be clearly identified as a medication error. 
(g) Lack of efficacy 
Lack of efficacy is suspected when the therapeutic result is not as expected, e.g., when patients 
with haemophilia experience continued bleeding despite the correct administration of 
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REGULATORY AND CLINICAL MONITORING 
The Site Principal Investigators (PIs) will perform source document verification of eligibility for all 
study enrollments. Verification also includes appropriate documentation of consent. Monitoring 
the timeliness of AE/SAE reporting will be done as events are reported. The study will also be 
monitored for compliance with the International Conference on Harmonization (ICH) Good 
Clinical Practice Guidelines (GCP). 
DATA COLLECTION 
Data Entry and Case Report Forms 
Clinical sites will enter data onto electronic Case Report Forms (eCRFs) via a secure, internet-
based electronic data capture (EDC) system. eCRFs must be completed for each subject 
screened or enrolled according to the subject’s source data on a per-visit basis. Authorized 
study personnel will each be granted access to the electronic data capture system via provision 
of a unique password-protected user ID that will limit access to enter and view data specifically 
for subjects enrolled at their site. Data should be entered into the EDC system within 3 business 
days of a subject’s visit. Sites will be supplied with a set of source document worksheets that 
correspond to the electronic case report form (eCRF). The worksheets will serve as source 
documents and are required to be used to enter data into the eCRFs. 
In addition, data will be collected from the subject’s medical record, subject reports, and subject 
diaries. Data on adherence to ITI dosing regimen will be collected from myCubixx via the portal. 
HRQoL questionnaires should be sent to the Study Coordinating Center for data entry in order 
to protect patients’ privacy. 
STATISTICAL ANALYSIS 
 
Randomization: Participants will be randomized 2:1. Treatment arm assignments (A-random lot, 
B-matched lot) will be determined by computer. The assignment will be communicated to the 
laboratory performing the matching denoting the subject’s code number and group assignment. 
 
Data Analysis: Analysis of categorical variables, matched/unmatched lots by time to effect will 
be performed using Kaplan-Meier plots and log-rank tests. Analysis of continuous and ranked 
categorical variables (e.g. degree of match) will use Cox regressions or accelerated time failure 
models. If multiple lots are required for a subject, multilevel models will be used. 
Power and Sample Size: A study with 110 participants will have the power to detect a hazard 
ratio as low as 2.5 at 90% with an α of 0.05. Given the initial hazard ratio estimates of 5 for time 
to BU < 0.6 and 2.5 for time to recovery > 80%, this should be sufficient. Assuming a drop-
out/loss rate of about 10%, the study would try to enroll 120 subjects. An estimate of the number 
needed to demonstrate that ITI using Wilate® is superior overall (percentage of subjects 
achieving successful ITI, power of 80% and α of 0.05) is greater than 700 making this as an 
endpoint unachievable. 
Interim Analysis: An interim analysis with the aim of possible early termination will use the alpha 
spending approach as described by DeMets and Lan.80 The Lan-DeMets boundary using the 
O’Brien-Fleming spending function, assuming that most subjects will have achieved criteria 1 or 


  
 
 
 
 
 
 
 
 
 
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2 by 6 months of treatment, evaluation 6 months after the 60th subject has been enrolled should 
include about 55% of the information for the trial and the level at which one could reject the null 
hypothesis (no difference between the two arms for a one-sided test at a final p < 0.05) is α < 
0.008. In the event that trial accrual is slow, an analysis could be performed after 40 subjects 
have completed at least 6 months of treatment but this would include only about 36% of the total 
information and the required α < 0.001.81 Any interim analysis will be evaluated by an 
independent data monitoring board. 
HUMAN SUBJECTS PROTECTION 
 
All aspects of this clinical trial will be conducted according to the protocol, relevant FDA 
regulations, ICH-GCP Guidelines, and HIPAA for protection of human subjects. IRB approval 
must be obtained by each participating site. A copy of the IRB approval letter and the approved 
consent document must be received and approved prior to enrollment of subjects by the site. 
Copies of approval letters for continuing review must be received by the Coordinating Center 
prior to expiration of IRB approval so that sites’ ability to enroll and treat participants is not 
interrupted. A copy of the IRB approval letter for each amendment must be received by the 
Coordinating Center in order for subjects to be enrolled on the protocol amendment. Continuing 
IRB review will occur annually or more frequently as determined by the IRB of Record for the 
site. 
 
Risk to the Subjects 
Subjects will be randomly assigned to the standard care or alternative arm of the trial. The risk 
to the subjects involves primarily the risk of bleeding with sustained inhibitor titer if they are 
randomized to the alternative arm of the trial, but this risk remains with the standard arm as well. 
Additional risks include: 1) minor risks related to venipuncture; 2) adverse reaction to Wilate®; 3) 
loss of anonymity. 
 
Adequacy of Protection against Risks 
The INITIATE trial will be designed and implemented with great concern for the welfare of 
participants. Subjects will be recruited by local clinical staff and should be well known to each 
center since they will already be receiving hemophilia care. If eligible, the participant or 
participant’s parent will be informed about the study and asked to participate. After detailed 
discussion of the protocol, they will be given a copy of the informed consent document for 
review. Participation is completely voluntary and parents may withdraw their child from the study 
at any time. In addition to parental consent, written or verbal assent will be obtained from 
subjects whenever required by the IRB of Record for the site. Subjects and families will be 
informed of any information that becomes available during the trial that might impact their 
continued participation. 
 
Protected Health Information (PHI): Subjects will be given code numbers and these numbers 
will be used to identify blood samples and matched/random lot allocation. This includes the drug 
distribution from ASD Healthcare to the distributing pharmacies and the information derived 
from the myCubixx refrigerator. 
 


  
 
 
 
 
 
 
 
 
 
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Oversight of the Study 
Steering Committee 
The INITIATE trial will receive overall guidance and oversight from a formal Steering 
Committee, consisting of the following members: Dr. Ducore, Dr. Thornburg, study site Principal 
Investigators (PIs) and a representative from the Central Lab. The entire Steering Committee 
will meet remotely twice during each year to discuss and provide direction for the INITIATE trial. 
Quarterly, the Steering Committee will have a telephone conference call to discuss problems 
and issues related to subject recruitment, enrollment, treatment, and data collection; minutes 
will be distributed. 
 
Study Coordinating Center 
The Study Coordinating Center will oversee the day-to-day issues and problems that arise 
during the INITIATE trial and will be critical to the smooth functioning of this clinical trial. 
 
The Study Coordinating Center will meet with site staff by teleconference on a weekly basis 
throughout the trial, with a formal agenda designed to anticipate and address clinical, logistical, 
and practical problems that are encountered. Site staff will provide a site-specific report during 
each teleconference meeting, updating the Coordinating Center project manager on subject 
accrual, enrollment progress, data entry, and adherence strategies. During teleconference 
meetings, site staff will report any technical problems with ITI as applicable.  Minutes from the 
weekly teleconferences will be distributed to each of the clinical sites. 
 
Potential Benefits of the Proposed Research to Subjects and Others 
Potential benefits to participants in this trial include the potential to achieve ITI success earlier 
and to have fewer bleeding episodes. 
 
 
Importance of the Knowledge to be Gained 
Inhibitors are associated with increased morbidity, mortality and associated costs. Determining 
an optimal ITI regimen has the potential to have an important impact. 
Ethics 
GCP and IRB Review 
Compliance with GCP guidelines for the conduct and monitoring of this clinical trial will occur 
through observation of the ethical and regulatory requirements presented in ICH E6, Good 
Clinical Practice: Consolidated Guideline. By signing this protocol, the investigator agrees to 
adhere to these requirements. The study (protocol, informed consent, advertisements, product 
package insert, and subject-facing material) should be reviewed and approved by the IRB of 
Record for each site. Changes to the protocol will be also be reviewed and approved by the IRB 
of Record for each site. Subjects must sign written informed consent prior to being screened, 
before undergoing any study procedures. 
 
The investigators and institutions affiliated with this study will permit trial-related monitoring, 
audits, IRB/IEC review, and regulatory inspection(s) by providing direct access to source 
documents. 


  
 
 
 
 
 
 
 
 
 
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Informed Consent 
A model informed consent will be prepared by the INITIATE Study Coordinating Center and 
subsequently provided to clinical centers for preparation of center-specific consent forms. A 
copy of each site’s IRB approved consent form will be maintained at the Study Coordinating 
Center, and a new consent and IRB review will be required for any changes in the protocol. 
Families will be provided with a copy of their signed consent document. The peripheral clinical 
site should follow the sample informed consent as closely as possible. The informed consent 
can be modified to include IRB required language; the template language should not be deleted. 
Subjects will be provided with a copy of the informed consent and printed materials that further 
explain the purpose of the study, the medication(s) used in the study, procedures, and 
assessments. Subjects will also be provided with the telephone numbers of the Principal 
Investigator and qualified personnel who can assist with their questions and concerns. 
Confidentiality 
To ensure confidentiality, all enrolled subjects will be assigned a unique identification number 
that will be used in all correspondence between clinical centers and the Study Coordinating 
Center. The DSMC advises on issues such as study design, power estimates, stopping rules, 
interim analyses, and adverse event reporting. Members of the DSMC also assess the 
seriousness of unexpected adverse events. When the results of the trial are published, each 
subject’s identity will remain confidential. 
Disclosure of Data 
The Principal Investigator, his or her staff and associates, and the appropriate regulatory 
agencies may use the information included in this protocol as necessary for the conduct of the 
trial and the safety of subjects. Data from the trial are confidential and may not be disclosed 
without the written permission of the Study Coordinating Center. 
Publication of Research Findings 
The results from this clinical trial have the potential for immediate public health applicability for 
the hemophilia community. A publications committee will be established to guide publications 
and authorship. Data analysis and manuscript preparation will occur during the last 6-12 months 
of the funding period. At the end of the trial, the main outcome paper will be submitted to a 
prestigious journal, such as the New England Journal of Medicine, British Journal of 
Hematology, or Blood. The trial results will be presented at the World Federation of Hemophilia 
meeting, the International Society of Haemostasis and Thrombosis (ISTH) meeting, the 
American Society of Pediatric Hematology/Oncology (ASPHO), and the American Society of 
Hematology (ASH). To educate allied health care professionals, the study results will be 
presented at Grand Rounds at the respective participating universities, plus the annual National 
Hemophilia Foundation Meeting. Other results generated from the trial that are not published in 
the main outcome manuscript will be submitted for publication in prestigious medical journals 
and presented at the scientific meetings listed above. ASPHO and ASH, organizations with 
which the investigators have a long-standing professional relationship, will be asked to assist in 
the educational effort of health care practitioners who care for subjects with hemophilia.  
 
 
 


  
 
 
 
 
 
 
 
 
 
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2010:1896-920.


  
 
 
 
 
 
 
 
 
 
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Appendix I: Schedule of Events 
 
Evaluation 
Eligibility Screening 
ITI 
Week 
Week -8 
to week -5 
Consent to 
week -5 
0 
2 
(+3 days) 
4 
(+3 days) 
8 
(+5 days) 
12 
(+5 days) 
16 
(+5 days) 
20 
(+5 days) 
24 
(+5 days) 
Signed informed consent 
document 
x 
 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
Clinical assessment* 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
Height and weight 
 
x 
 
 
 
 
 
 
x 
 
FVIII reactivity to Wilate®   
 
x 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
Antibody epitopes on 
FVIIIC 
 
x 
 
 
 
 
 
 
 
 
Immunogenotyping/HLA 
genotypingC 
 
x 
 
 
 
 
 
 
 
 
Factor VIII genetic 
testingC  
 
x 
 
 
 
 
 
 
 
 
VWF activity/Ag 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FVIII inhibitor titer 
 
x 
x 
x 
x 
x 
x 
x 
x 
xD 
FVIII Assay 
 
 
 
 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
FVIII trough level  
 
 
 
 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
FVIII recovery 
 
 
 
 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
Adherence assessmentA 
 
 
 
 
x 
x 
x 
x 
x 
x 
Dispense/collect diaries 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HRQoL assessmentB 
 
x 
 
 
 
 
 
 
 
 
ITI=immune tolerance induction 
∆Update if participant turns 18 years old  
 
*Clinical assessments must be done at clinical site every 8 weeks after the week 4 visit; telephone visits may be done 4 weeks + 5 days after each in-person clinical site visit. All clinical assessments will 
include con med and adverse event follow-up.  
 
 
 
 
^Repeat for participants who deplete originally assigned batch; should be done 3 weeks prior to lot depletion 
ⱡAssess FVIII recovery once FVIII inhibitor negative 
ⱡAssess FVIII 6 + 2 hour and 22 + 2 hour trough level once FVIII recovery at ≥66%  
ⱡ Perform FVIII assay as part of FVIII half-life and recovery assays 
A Adherence assessments will be based on patient reports 
B HRQOL assessment will be performed at the start of the study, at the first clinical evaluation after negative titer documented, and at study exit. 
C Optional – collect only if consent is given by the subject 
D Participants in the standard treatment arm who still have an inhibitor titer >0.6 may be switched to the alternative treatment arm.They will be treated as new participants who have failed prior ITI and a 
second individualized lot selection will be performed using the original plasma sample provided at baseline.  


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 50 of 59 
Version 3.0 31-Jul-2018 
Schedule of Study Evaluations (cont) 
Evaluation 
ITI 
Follow-up after Complete or Partial Success 
Week 
28 
(+5 
days) 
32 
(+5 
days) 
36 
(+5 
days) 
40 
(+5 
days) 
44 
(+5 
days) 
48 
(+5 
days) 
52 
(+5 
days) 
56 
(+5 
days) 
60 
(+5 
days) 
64 
(+5 
days) 
68 
(+5 
days) 
72 
(+5 
days) 
76 
(+5 
days) 
+8 
(+5 
days) 
+16 
(+5 
days) 
+24 
(+5 
days) 
+32 
(+5 
days) 
+40 
(+5 
days) 
+48 
(+5 
days) 
+52 
(+5 
days) 
Signed informed 
consent 
document 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
∆ 
Clinical 
assessment*  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height/weight 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
FVIII reactivity 
to Wilate® 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
^ 
VWF activity/Ag 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVIII Inhibitor 
titer 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FVIII Assay 
x 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
 
 
 
 
 
 
 
FVIII trough 
level  
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
 
 
 
 
 
 
 
FVIII recovery 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
ⱡ 
 
 
 
 
 
 
 
Adherence 
assessmentA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Dispense/collect 
diaries 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HRQoL 
assessmentB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ITI=immune tolerance induction 
∆Update if participant turns 18 years old 
 
*Clinical assessments must be done at clinical site every 8 weeks after the week 4 visit; telephone visits may be done 4 weeks + 5 days after each in-person clinical site visit. All clinical assessments will include con med and adverse 
event follow-up.  
^Repeat for participants who deplete originally assigned batch; should be done 3 weeks prior to lot depletion 
ⱡAssess FVIII recovery once FVIII inhibitor negative 
ⱡAssess FVIII 6 + 2 hour and 22 + 2 trough level once FVIII recovery at ≥66%ⱡ Perform FVIII assay as part of FVIII half-life and recovery assays 
A Adherence assessments will be based on patient reports 
B HRQOL assessment will be performed at the start of the study, at the first clinical evaluation after negative titer documented, and at study exit.


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 51 of 59 
Version 3.0 31-Jul-2018 
Appendix II. Dosing Chart 
 
 
 
  
 
BW 
[kg] 
Dose [IU/kg/day] 
Total dose [IU]/day 
Selected 
total dose 
[IU] 
Actual 
dose 
[IU/kg] 
Batch 
duration 
[months] 
150 
Variable 
200 
Range 
5 
150 
180 
200 
750 
900 
1000 
1000 
200 
56.7 
6 
150 
180 
200 
900 
1080 
1200 
1000 
167 
56.7 
7 
150 
180 
200 
1050 
1260 
1400 
1500 
214 
37.8 
8 
150 
180 
200 
1200 
1440 
1600 
1500 
188 
37.8 
9 
150 
180 
200 
1350 
1620 
1800 
1500 
167 
37.8 
10 
150 
180 
200 
1500 
1800 
2000 
2000 
200 
28.3 
11 
150 
180 
200 
1650 
1980 
2200 
2000 
182 
28.3 
12 
150 
180 
200 
1800 
2160 
2400 
2000 
167 
28.3 
13 
150 
180 
200 
1950 
2340 
2600 
2000 
153 
28.3
14 
150 
180 
200 
2100 
2520 
2800 
3000 
214 
18.9 
15 
150 
185 
200 
2250 
2775 
3000 
3000 
200 
18.9 
16 
150 
185 
200 
2400 
2960 
3200 
3000 
188 
18.9 
17 
150 
185 
200 
2550 
3145 
3400 
3000 
176 
18.9 
18 
150 
185 
200 
2700 
3330 
3600 
3000 
167 
18.9 
19 
150 
185 
200 
2850 
3515 
3800 
4000 
211 
14.2 
20 
150 
185 
200 
3000 
3700 
4000 
4000 
200 
14.2 
21 
150 
185 
200 
3150 
3885 
4200 
4000 
190 
14.2 
22 
150 
185 
200 
3300 
4070 
4400 
4000 
182 
14.2 
23 
150 
185 
200 
3450 
4255 
4600 
4000 
174 
14.2 
24 
150 
185 
200 
3600 
4440 
4800 
4000 
167 
14.2 
25 
150 
185 
200 
3750 
4625 
5000 
5000 
200 
11.3 
26 
150 
185 
200 
3900 
4810 
5200 
5000 
192 
11.3 
27 
150 
185 
200 
4050 
4995 
5400 
5000 
185 
11.3 
28 
150 
185 
200 
4200 
5180 
5600 
5000 
179 
11.3 
29 
150 
185 
200 
4350 
5365 
5800 
5000 
172 
11.3 
30 
150 
190 
200 
4500 
5700 
6000 
6000 
200 
9.4 
31 
150 
190 
200 
4650 
5890 
6200 
6000 
194 
9.4 
32 
150 
190 
200 
4800 
6080 
6400 
6000 
188 
9.4 
33 
150 
190 
200 
4950 
6270 
6600 
6000 
182 
9.4 
34 
150 
190 
200 
5100 
6460 
6800 
6000 
176 
9.4 
35 
150 
190 
200 
5250 
6650 
7000 
7000 
200 
8.1 
36 
150 
190 
200 
5400 
6840 
7200 
7000 
194 
8.1 
37 
150 
190 
200 
5550 
7030 
7400 
7000 
189 
8.1 
38 
150 
190 
200 
5700 
7220 
7600 
7000 
184 
8.1 
39 
150 
190 
200 
5850 
7410 
7800 
7000 
179 
8.1 
40 
150 
190 
200 
6000 
7600 
8000 
8000 
200 
7.1 
41 
150 
190 
200 
6150 
7790 
8200 
8000 
195 
7.1 
 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 52 of 59 
Version 3.0 31-Jul-2018 
BW 
[kg] 
Dose [IU/kg] 
Total dose [IU] 
Selected 
total dose 
[IU] 
Actual 
dose 
[IU/kg] 
Batch 
duration 
[months] 
150 
Variable 
200 
Range 
42 
150 
190 
200 
6300 
7980 
8400 
8000 
190 
7.1 
43 
150 
190 
200 
6450 
8170 
8600 
8000 
186 
7.1 
44 
150 
190 
200 
6600 
8360 
8800 
8000 
182 
7.1 
45 
150 
190 
200 
6750 
8550 
9000 
9000 
200 
6.3 
46 
150 
190 
200 
6900 
8740 
9200 
9000 
196 
6.3 
47 
150 
190 
200 
7050 
8930 
9400 
9000 
191 
6.3 
 
48 
150 
190 
200 
7200 
9120 
9600 
9000 
188 
6.3 
49 
150 
190 
200 
7350 
9310 
9800 
9000 
184 
6.3 
50 
150 
190 
200 
7500 
9500 
10000 
10000 
200 
5.7 
51 
150 
190 
200 
7650 
9690 
10200 
10000 
196 
5.7 
52 
150 
190 
200 
7800 
9880 
10400 
10000 
192 
5.7 
53 
150 
190 
200 
7950 
10070 
10600 
10000 
189 
5.7 
54 
150 
190 
200 
8100 
10260 
10800 
10000 
185 
5.7 
55 
150 
190 
200 
8250 
10450 
11000 
10000 
182 
5.7 
56 
150 
190 
200 
8400 
10640 
11200 
11000 
196 
5.2 
57 
150 
190 
200 
8550 
10830 
11400 
11000 
193 
5.2 
58 
150 
190 
200 
8700 
11020 
11600 
11000 
190 
5.2 
59 
150 
190 
200 
8850 
11210 
11800 
11000 
186 
5.2 
60 
150 
195 
200 
9000 
11700 
12000 
12000 
200 
4.7 
61 
150 
195 
200 
9150 
11895 
12200 
12000 
197 
4.7 
62 
150 
195 
200 
9300 
12090 
12400 
12000 
194 
4.7 
63 
150 
195 
200 
9450 
12285 
12600 
12000 
190 
4.7 
64 
150 
195 
200 
9600 
12480 
12800 
12000 
188 
4.7 
65 
150 
195 
200 
9750 
12675 
13000 
13000 
200 
4.4 
66 
150 
195 
200 
9900 
12870 
13200 
13000 
197 
4.4 
67 
150 
195 
200 
10050 
13065 
13400 
13000 
194 
4.4 
68 
150 
195 
200 
10200 
13260 
13600 
13000 
191 
4.4 
69 
150 
195 
200 
10350 
13455 
13800 
13000 
188 
4.4 
70 
150 
195 
200 
10500 
13650 
14000 
14000 
200 
4.0 
71 
150 
195 
200 
10650 
13845 
14200 
14000 
197 
4.0 
72 
150 
195 
200 
10800 
14040 
14400 
14000 
194 
4.0 
73 
150 
195 
200 
10950 
14235 
14600 
14000 
192 
4.0 
74 
150 
195 
200 
11100 
14430 
14800 
14000 
189 
4.0 
75 
150 
195 
200 
11250 
14625 
15000 
15000 
200 
3.8 
76 
150 
195 
200 
11400 
14820 
15200 
15000 
197 
3.8 
77 
150 
195 
200 
11550 
15015 
15400 
15000 
195 
3.8 
78 
150 
195 
200 
11700 
15210 
15600 
15000 
192 
3.8 
79 
150 
195 
200 
11850 
15405 
15800 
15000 
190 
3.8 
 
 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 53 of 59 
Version 3.0 31-Jul-2018 
BW 
[kg] 
Dose [IU/kg] 
Total dose [IU] 
Selected 
total dose 
[IU] 
Actual 
dose 
[IU/kg] 
Batch 
duration 
[months] 
150 
Variable 
200 
Range 
80 
150 
195 
200 
12000 
15600 
16000 
16000 
200 
3.5 
81 
150 
195 
200 
12150 
15795 
16200 
16000 
198 
3.5 
82 
150 
195 
200 
12300 
15990 
16400 
16000 
195 
3.5 
83 
150 
195 
200 
12450 
16185 
16600 
16000 
193 
3.5 
84 
150 
195 
200 
12600 
16380 
16800 
16000 
190 
3.5 
85 
150 
195 
200 
12750 
16575 
17000 
17000 
200 
3.3 
86 
150 
195 
200 
12900 
16770 
17200 
17000 
198 
3.3 
87 
150 
195 
200 
13050 
16965 
17400 
17000 
195 
3.3 
88 
150 
195 
200 
13200 
17160 
17600 
17000 
193 
3.3 
89 
150 
195 
200 
13350 
17355 
17800 
17000 
191 
3.3 
90 
150 
195 
200 
13500 
17550 
18000 
18000 
200 
3.1 
91 
150 
195 
200 
13650 
17745 
18200 
18000 
198 
3.1 
92 
150 
195 
200 
13800 
17940 
18400 
18000 
196 
3.1 
93 
150 
195 
200 
13950 
18135 
18600 
18000 
194 
3.1 
94 
150 
195 
200 
14100 
18330 
18800 
18000 
191 
3.1 
 
95 
150 
195 
200 
14250 
18525 
19000 
19000 
200 
3.0 
96 
150 
195 
200 
14400 
18720 
19200 
19000 
198 
3.0 
97 
150 
195 
200 
14550 
18915 
19400 
19000 
196 
3.0 
98 
150 
195 
200 
14700 
19110 
19600 
19000 
194 
3.0 
99 
150 
195 
200 
14850 
19305 
19800 
19000 
192 
3.0 
100 
150 
195 
200 
15000 
19500 
20000 
20000 
200 
2.8 
101 
150 
195 
200 
15150 
19695 
20200 
20000 
198 
2.8 
102 
150 
195 
200 
15300 
19890 
20400 
20000 
196 
2.8 
103 
150 
195 
200 
15450 
20085 
20600 
20000 
194 
2.8 
104 
150 
195 
200 
15600 
20280 
20800 
20000 
192 
2.8 
105 
150 
195 
200 
15750 
20475 
21000 
20000 
190 
2.8 
106 
150 
195 
200 
15900 
20670 
21200 
20000
189
2.8 
107 
150 
195 
200 
16050 
20865 
21400 
20000
187
2.8 
108 
150 
195 
200 
16200 
21060 
21600 
20000 
185 
2.8 
109 
150 
195 
200 
16350 
21255 
21800 
20000 
183
2.8 
110 
150 
195 
200 
16500 
21450 
22000 
20000 
182
2.8 
111 
150 
195 
200 
16650 
21645 
22200 
20000 
180
2.8 
112 
150 
195 
200 
16800 
21840 
22400 
20000 
179
2.8 
113 
150 
195 
200 
16950 
22035 
22600 
20000 
177
2.8 
114 
150 
195 
200 
17100 
22230 
22800 
20000 
175
2.8 
115 
150 
195 
200 
17250 
22425 
23000 
20000 
174
2.8 
116 
150 
195 
200 
17400 
22620 
23200 
20000 
172
2.8 
117 
150 
195 
200 
17550 
22815 
23400 
20000 
171
2.8 
118 
150 
195 
200 
17700 
23010 
23600 
20000 
169
2.8 
 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 54 of 59 
Version 3.0 31-Jul-2018 
BW 
[kg] 
Dose [IU/kg] 
Total dose [IU] 
Selected 
total dose 
[IU] 
Actual 
dose 
[IU/kg] 
Batch 
duration 
[months] 
150 
Variable 
200 
Range 
119 
150 
195 
200 
17850 
23205 
23800 
20000 
168
2.8 
120 
150 
195 
200 
18000 
23400 
24000 
20000 
167
2.8 
121 
150 
195 
200 
18150 
23595 
24200 
20000 
165
2.8 
122 
150 
195 
200 
18300 
23790 
24400 
20000 
164
2.8 
123 
150 
195 
200 
18450 
23985 
24600 
20000 
163
2.8 
124 
150 
195 
200 
18600 
24180 
24800 
20000 
161
2.8 
125 
150 
195 
200 
18750 
24375 
25000 
20000 
160
2.8 
Max 
214 
56.7 
Min 
153 
2.8 
Mean 
188 
8.7 
Median 
191 
4.7 
 
* New lot should be selected 8 weeks prior to end of current supply. Patients weighing more than 35 kg may need more than 1 lot 
during ITI and will need more samples collected at the beginning of the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 55 of 59 
Version 3.0 31-Jul-2018 
Appendix III: Subject Flow Diagram 
 
 
 
CS Complete Success 
PS Partial Success 
PR Partial Response 
PF Partial Failure 
 
 
CF Complete Failure 
 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 56 of 59 
Version 3.0 31-Jul-2018 
Appendix IV: Dose Reduction for Participants on Hemlibra® 
 
BW [kg] 
Dose [50IU/kg 
QOD] 
Selected Total Dose [IU] 
Actual Dose [IU/kg] 
Batch Duration [months] 
5 
250 
500 
100 
267 
6 
300 
500 
83 
267 
7 
350 
500 
71 
267 
8 
400 
500 
63 
267 
9 
450 
500 
56 
267 
10 
500 
500 
50 
267 
11 
550 
500 
45 
267 
12 
600 
500 
42 
267 
13 
650 
1000 
77 
133 
14 
700 
1000 
71 
133 
15 
750 
1000 
67 
133 
16 
800 
1000 
63 
133 
17 
850 
1000 
59 
133 
18 
900 
1000 
56 
133 
19 
950 
1000 
53 
133 
20 
1000 
1000 
50 
133 
21 
1050 
1000 
48 
133 
22 
1100 
1000 
45 
133 
23 
1150 
1000 
43 
133 
24 
1200 
1000 
42 
133 
25 
1250 
1000 
40 
133 
26 
1300 
2000 
77 
67 
27 
1350 
2000 
74 
67 
28 
1400 
2000 
71 
67 
29 
1450 
2000 
69 
67 
30 
1500 
2000 
67 
67 
31 
1550 
2000 
65 
67 
32 
1600 
2000 
63 
67 
33 
1650 
2000 
61 
67 
34 
1700 
2000 
59 
67 
35 
1750 
2000 
57 
67 
36 
1800 
2000 
56 
67 
37 
1850 
2000 
54 
67 
38 
1900 
2000 
53 
67 
39 
1950 
2000 
51 
67 
40 
2000 
2000 
50 
67 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 57 of 59 
Version 3.0 31-Jul-2018 
BW [kg] 
Dose [50IU/kg 
QOD] 
Selected Total Dose [IU] 
Actual Dose [IU/kg] 
Batch Duration [months] 
41 
2050 
2000 
49 
67 
42 
2100 
2000 
48 
67 
43 
2150 
2000 
47 
67 
44 
2200 
3000 
68 
44 
45 
2250 
3000 
67 
44 
46 
2300 
3000 
65 
44 
47 
2350 
3000 
64 
44 
48 
2400 
3000 
63 
44 
49 
2450 
3000 
61 
44 
50 
2500 
3000 
60 
44 
51 
2550 
3000 
59 
44 
52 
2600 
3000 
58 
44 
53 
2650 
3000 
57 
44 
54 
2700 
3000 
56 
44 
55 
2750 
3000 
55 
44 
56 
2800 
3000 
54 
44 
57 
2850 
3000 
53 
44 
58 
2900 
3000 
52 
44 
59 
2950 
3000 
51 
44 
60 
3000 
3000 
50 
44 
61 
3050 
3000 
49 
44 
62 
3100 
3000 
48 
44 
63 
3150 
3000 
48 
44 
64 
3200 
4000 
63 
33 
65 
3250 
4000 
62 
33 
66 
3300 
4000 
61 
33 
67 
3350 
4000 
60 
33 
68 
3400 
4000 
59 
33 
69 
3450 
4000 
58 
33 
70 
3500 
4000 
57 
33 
71 
3550 
4000 
56 
33 
72 
3600 
4000 
56 
33 
73 
3650 
4000 
55 
33 
74 
3700 
4000 
54 
33 
75 
3750 
4000 
53 
33 
76 
3800 
4000 
53 
33 
77 
3850 
4000 
52 
33 
78 
3900 
4000 
51 
33 
79 
3950 
4000 
51 
33 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 58 of 59 
Version 3.0 31-Jul-2018 
BW [kg] 
Dose [50IU/kg 
QOD] 
Selected Total Dose [IU] 
Actual Dose [IU/kg] 
Batch Duration [months] 
80 
4000 
4000 
50 
33 
81 
4050 
4000 
49 
33 
82 
4100 
4000 
49 
33 
83 
4150 
4000 
48 
33 
84 
4200 
4000 
48 
33 
85 
4250 
5000 
59 
27 
86 
4300 
5000 
58 
27 
87 
4350 
5000 
57 
27 
88 
4400 
5000 
57 
27 
89 
4450 
5000 
56 
27 
90 
4500 
5000 
56 
27 
91 
4550 
5000 
55 
27 
92 
4600 
5000 
54 
27 
93 
4650 
5000 
54 
27 
94 
4700 
5000 
53 
27 
95 
4750 
5000 
53 
27 
96 
4800 
5000 
52 
27 
97 
4850 
5000 
52 
27 
98 
4900 
5000 
51 
27 
99 
4950 
5000 
51 
27 
100 
5000 
5000 
50 
27 
101 
5050 
5000 
50 
27 
102 
5100 
5000 
49 
27 
103 
5150 
5000 
49 
27 
104 
5200 
5000 
48 
27 
105 
5250 
5000 
48 
27 
106 
5300 
6000 
57 
22 
107 
5350 
6000 
56 
22 
108 
5400 
6000 
56 
22 
109 
5450 
6000 
55 
22 
110 
5500 
6000 
55 
22 
111 
5550 
6000 
54 
22 
112 
5600 
6000 
54 
22 
113 
5650 
6000 
53 
22 
114 
5700 
6000 
53 
22 
115 
5750 
6000 
52 
22 
116 
5800 
6000 
52 
22 
117 
5850 
6000 
51 
22 
118 
5900 
6000 
51 
22 


  
 
 
 
 
 
 
 
 
 
INITIATE Trial 
  
    Page 59 of 59 
Version 3.0 31-Jul-2018 
BW [kg] 
Dose [50IU/kg 
QOD] 
Selected Total Dose [IU] 
Actual Dose [IU/kg] 
Batch Duration [months] 
119 
5950 
6000 
50 
22 
120 
6000 
6000 
50 
22 
121 
6050 
6000 
50 
22 
122 
6100 
6000 
49 
22 
123 
6150 
6000 
49 
22 
124 
6200 
6000 
48 
22 
125 
6250 
6000 
48 
22 
Max 
100 
267 
Mean 
56 
63 
Min 
40 
22 
 

ICF_001.pdf: 
Permission to Take Part in a Human Research Study 
Page 1 of 12 
 
For IRB stamp and version date only 
 
 
 
 
 
 
ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
Title of research study: INdividualized ITI based on fviii(ATE) protection by 
VWF (INITIATE) 
Investigators: 
Jonathan Ducore, MD, MPH 
Department of Pediatrics (UC Davis) 
Telephone Number: (916) 734-2781 
Research Team: (916) 734-3469 
 
Courtney Thornburg, MD 
Department of Pediatrics (UC San Diego) 
Telephone Number: (858) 966-5811 
___________________________________________________________________________________________ 
This form is being reviewed with (check all that apply): 
 An adult (age 18 years and up) who may become a study participant.  
 The parent or legal guardian (age 18 years and up) of a minor under 18 years of age who may become a 
study participant. Please note that “you” means your child because you are consenting for your child. 
___________________________________________________________________________________________ 
Why am I being invited to take part in a research study? 
We invite you to take part in a research study because you have congenital Hemophilia A, FVIII activity 
≤2%, and a historical high-titer inhibitor. This consent document is for use in a research study that will 
involve research participants who may or may not have the capacity to consent to their participation. In 
this consent document, “you” refers to the research participant. If you are a parent or legal guardian, 
please remember that “you” refers to your child. 
What should I know about a research study? 
(Experimental Subject's Bill of Rights)  
• Someone will explain this research study to you, including: 
o The nature and purpose of the research study. 
o The procedures to be followed. 
o Any drug or device to be used.  
o Any common or important discomforts and risks. 
o Any benefits you might expect. 
o Other procedures, drugs, or devices that might be helpful, and their risks and benefits 
compared to this study.  
o Medical treatment, if any, that is available for complications.  
• Whether or not you take part is up to you. 
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
• You can choose without force, fraud, deceit, duress, coercion, or undue influence. 
• You can choose not to take part. 
• You can agree to take part now and later change your mind. 
• Whatever you decide it will not be held against you. 
• You can ask all the questions you want before you decide. 
• If you agree to take part, you will be given a signed and dated copy of this document.  
• If you agree to take part, you will be given a copy of this document.  
 
If you decide to take part in this research study, you will be asked to sign this consent document 
before any study-related activities are performed. You will receive a copy of this signed consent 
document for your records. 
Who can I talk to? 
If you have questions, concerns, or complaints, or think the research has hurt you, talk to the research 
team listed at the top of this form. 
For non-emergency issues you can call the UCDMC Hospital Operator (916-734-2011), tell the 
Operator you are participating in a research study and you wish to talk to the hematologist on call. In the 
case of an emergency, dial 911 from any phone. 
This research has been reviewed and approved by an Institutional Review Board (“IRB”). Information to 
help you understand research is on-line at http://www.research.ucdavis.edu/policiescompliance/irb-
admin/.You may talk to a IRB staff member at (916) 703-9151, hs-irbadmin@ucdavis.edu, or 2921 
Stockton Blvd, Suite 1400, Room 1429, Sacramento, CA 95817 for any of the following: 
• Your questions, concerns, or complaints are not being answered by the research team. 
• You cannot reach the research team. 
• You want to talk to someone besides the research team. 
• You have questions about your rights as a research subject. 
• You want to get information or provide input about this research. 
Why is this research being done? 
Many people being treated for severe Hemophilia A experience serious complications due to antibodies 
that form during treatment. Immune Tolerance Induction (ITI) therapy is a program of regular infusions 
over a prolonged period of time - from a few months to a few years - to remove these antibodies and 
improve overall treatment. This research will study the effectiveness of ITI, as well as the best ways to 
implement ITI to improve the treatment of people with severe Hemophilia A. 
The rationale for this study is that an optimal regimen for ITI has not been identified, and patients with 
Hemophilia A and inhibitors have high rates of illness, mortality, and associated costs. We hope to learn 
if there are potential advantages of using a patient-specific laboratory test called batch-selection to 
decrease the time to success in Immune Tolerance Induction (ITI) for hemophilia A patients with 
inhibitors to FVIII. 
Participants in this study will be randomized on a two-to-one basis between one of two study arms, 
matched lot selection (alternative treatment arm) and random lot selection (standard treatment arm, 
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
current US clinical practice in ITI). The purpose of this study is to compare the time to achieve negative 
inhibitor (<0.6 BU) between matched lot selection to random lot selection.  
OPTIONAL GENETIC RESEARCH: 
There is an opportunity for us to comprehensively study certain aspects of inhibitors and the induction of 
immune tolerance through this study. This would require us to collect an additional 2 teaspoons of blood 
during your screening visit. This optional research will look at genetic risk factors and a person’s 
response to immune tolerance induction and genetic testing to identify the causative factor VIII 
mutation.   
If you agree to participate in the optional research, please initial here: __________ 
If you do NOT want to participate in the optional research, please initial here: ____________ 
How long will the research last? 
We expect that you will be in this research study for up to 36 months.  
How many people will be studied? 
We expect up to 6 people here will be in this research study out of 120 people in the entire study 
nationally.  
What happens if I say yes, I want to be in this research? 
Before any study procedures begin, you will be asked to sign this consent form. The study doctor will 
examine you and ask you questions to determine if you are eligible for the study. If blood samples were 
already collected prior to signing this consent form, then you may not need to have additional blood 
samples collected for the screening visit activities described below. 
If you have had any prior ITI therapy, the prior ITI regimen must have been discontinued within 1 
month of study enrollment unless there is clear evidence of ITI failure with no reduction in inhibitor titer 
over the past 2 months.  
The screening visit should take place within 35 to 56 days of the baseline visit (a period of time known 
as the screening period). Blood samples for laboratory tests no more than 35 days before the baseline 
visit. The tests and assessments that you will have are shown in Table 1.You will have evaluations on a 
monthly basis until ITI is completed. Evaluations must be performed at the clinical site at least every 8 
weeks. Clinical evaluations will be performed by telephone call 4 weeks after every in-person visit 
performed at the clinical site. 
 
If at 6 months it is found that you still have inhibitors and you are in the standard treatment arm (random 
lot selection), you may be switched to the alternative treatment arm of the study.  
 
 
 
 
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
 
 
Table 1. Assessments performed at each visit 
Study visit 
Duration or time point 
Procedures 
Screening 
period 
Up to 56 or 35 days  
• Sign the Informed Consent Form (up to 56 days) 
• Check whether the study is right for you (up to 56 
days) 
• Check of your medical history (up to 35 days) 
• Questions about whether you have received any other 
medications or non-drug therapies (up to 35 days) 
• Clinical information will be collected (up to 35 days) 
• Receive the patient diary and training on its use (up to 
35 days) 
• Quality of Life assessment (up to 35 days) 
• Laboratory evaluations (up to 35 days) 
• Weight and height measurement (up to 35 days) 
• We will determine the size of the study-specific 
refrigerator you will use and we will arrange for it to 
be sent to your home 
• Randomization to treatment arm 
Immune 
Tolerance 
Induction 
treatment period 
visits 
 
and 
 
Follow-up after 
complete or 
partial success  
• Day 0 (Baseline Visit in-
person) 
• Week 2 (in- person) 
• Week 4 (in-person) 
• Every 4 weeks after week 4 
(in-person or phone) 
 
 
 
• 
Every 8 weeks after 
complete or partial success 
(in-person or phone) 
 
 
Some or all of the following may happen at your visit:  
• 
Check whether the study is right for you 
• 
Sign the Informed Consent Form (if a minor child 
participant turns 18 years old) 
• 
You will start Immune Tolerance Induction treatment 
• 
Review of patient diary and discussion of any 
bleeding episodes and their treatment 
• 
Check of your medical history 
• 
Questions about whether you have received any other 
medications or non-drug therapies 
• 
Quality of Life assessment (as applicable) 
• 
Laboratory evaluations 
• 
Weight and height measurement as applicable 
• 
Assessment of your compliance with your ITI dosing 
regimen 
• 
Check your supply of Wilate®  
• 
Collect empty vials and boxes of Wilate®  
 
The assessments described in Table 1 are described below.  
 
The following clinical information will be collected during the screening period: 
a) 
Hemophilia history 
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
b) 
Current and prior hemophilia treatment information 
c)  
Blood tests 
 
The following information will be collected during your follow-up visits: 
• 
Concomitant medications 
• 
Medical history 
• 
Bleeding history 
• 
Quality of life (as applicable) 
• 
ITI-related adverse events and serious adverse events 
• 
Height/weight (as indicated in the schedule of events) 
• 
Diary information 
 
Questions about your health and medications 
The study doctor will ask if you have experienced any changes in your health, or any new symptoms 
since your last visit. They will also ask if you have taken any new medications (including prescription, 
over-the-counter, or other medications) since your last visit. 
Laboratory evaluations 
Blood samples will be collected to conduct blood tests. Approximately 21 mL (about 4 teaspoons) of 
blood will be collected during the screening visit. If you opt into the optional genetic testing, an 
additional 5.5 mL (about 1 teaspoon) will be collected. 
 
During the Immune Tolerance Induction (ITI) and Follow-Up portion, approximately 6mL (about 2 
teaspoons) will be collected each time a laboratory evaluation is performed.  
 
Blood tests will be done based on response to ITI. 
Review of patient diary  
Throughout study participation, you will be asked to fill out a patient diary. You will be given the diary 
during the screening visit, and it will be reviewed at each subsequent study center visit. You will be 
shown how to use the diary, in which you will need to record the following information: 
• 
Information about Wilate® infusions 
• 
Details of bleeding episodes and response to treatment, including the location, type, and severity 
of the bleed; the date and time of its onset and resolution; the date and time of each 
infusion/injection required to stop the bleed 
• 
Whether you experienced any untoward events. 
The diary will be collected from you at every in-person visit and a new diary will be dispensed. 
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
 
Randomization 
The treatment you get will be chosen by chance, like flipping a coin. Neither you nor the study doctor 
will choose what treatment you get. You will have a two to one (2:1) chance of being given the 
alternative treatment over the standard treatment. Neither you nor the study doctor will know which 
treatment you are getting.  
Wilate® will be stored at your house in the myCubixx refrigerator or in your own refrigerator. The 
MyCubixx refrigerator will be provided by ASD Healthcare. 
The research team will notify ASD Healthcare of your enrollment into the study in a manner that does 
not include your name, address, or other identifying information. ASD Healthcare will arrange, through 
a third party affiliate, for a myCubixx device to be delivered to and installed at your house. The research 
team will assist ASD Healthcare in arranging for the delivery of the myCubixx device to your house 
upon enrollment and the return of the myCubixx device upon termination of the study.  
What are my responsibilities if I take part in this research? 
If you take part in this research, you will be responsible to:  
• 
Report to the study clinic for all scheduled visits, lab draws,  and other visits as requested by the 
study staff.  
• 
Comply with all instructions provided by the doctor at the study site. 
• 
Follow instructions for keeping an accurate study diary. 
• 
Bring all empty vials and boxes of Wilate® to all your visits. 
• 
Report any changes in your symptoms or in how you feel.  Tell the doctor if you have seen 
another doctor, had a visit to the Emergency Room, or if you were admitted to the hospital.  
It is important that you immediately report any new symptoms or worsening of symptoms that you have 
to the study staff so they may follow you appropriately. 
If you take any of the following products, you are required to report them to your study doctor or study 
staff: 
• 
Medications that are prescribed by any doctor. 
• 
Over-the-counter medications. 
• 
Vitamins and dietary supplements. 
Any medications you take during the study will be recorded by the study staff to ensure your safety and 
well-being. You should call the study doctor before taking any new medication. 
You must inform the Investigator if you anticipate any changes to your routine medication(s). Usage of 
clotting factors (date, dosage, reason) will be recorded in the study diaries.  
What happens if I do not want to be in this research? 
You may decide not to take part in the research and it will not be held against you.   Participation in this 
study is voluntary. You are free to refuse to participate or stop taking part in the study at any time 
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
without any penalty or loss of benefits to which you are otherwise entitled. Your decision to participate 
or not participate will in no way affect your current or future treatment. You will be given all the needed 
time and opportunity to ask questions about the details of this study and to decide if you want to 
participate.  
There are options for you other than this research study including: 
• 
Not participating in this study. 
• 
Getting standard treatment for your condition without being in a study. 
• 
Getting a different experimental treatment or taking part in another study. 
What happens if I say yes, but I change my mind later? 
You can leave the research at any time and it will not be held against you. Your participation can be 
stopped safely. You will be asked to return to the study center for a final safety evaluation. Please 
consult with your study doctor to discuss the safest way to withdraw from the study if you wish to leave 
early.  
If you stop being in the research, already collected data may not be removed from the study database. 
You will be asked whether the investigator can collect data from your routine medical care. If you agree, 
this data will be handled the same as research data. 
 
Is there any way being in this study could be bad for me? 
Your study doctor /study staff will routinely follow-up with you to ensure the risks and/or benefits are 
monitored. 
Allergic reactions: Any medicine which is prepared from human blood and which is injected into a vein 
(administered intravenously), such as Wilate®, can cause allergic reactions. Please pay attention to early 
signs of allergic reactions (hypersensitivity), such as hives, skin rash, tightness of the chest, wheezing, 
low blood pressure, or anaphylaxis (when any or all of the above symptoms develop rapidly and are 
intense). If these symptoms occur, stop the injection immediately and contact the study doctor. These 
reactions have been found to be uncommon, i.e., they may affect up to 1 in 100 people. 
Transmission of infection: When medicines are made from human blood, certain measures are put in 
place to prevent infections from being passed on to patients. These measures include careful selection of 
blood and plasma donors to make sure donors at risk of carrying infections are ex-cluded, the testing of 
each donation and pools of plasma for signs of infections, and manufacturing steps that can inactivate or 
remove viruses. Despite these measures, when medicines prepared from human blood are administered, 
the possibility of passing on infection cannot be totally ex-cluded. This also applies to any unknown or 
emerging viruses or other types of infections. The measures taken are considered effective for enveloped 
viruses, such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and for 
the non-enveloped hepatitis A virus. The measures taken may be of limited value against non-enveloped 
viruses such as parvovirus B19.  
Wilate® may increase the risk of thromboembolic (clotting) events.  
 
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ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
Blood Draw Risks: Using a needle to remove blood from a vein is called “a blood draw.” It may be 
necessary to try more than once. A new needle will be used for each blood draw. Blood samples will be 
taken throughout the study. You might feel pain or be light-headed from this. You may experience some 
temporary discomfort, bleeding, bruising, swelling or rarely, infection, at the site of a needle stick. 
A total of about 2 teaspoons of blood will be collected at each clinic visit. 
Randomization: Patients will be assigned to a treatment program by chance, and the treatment a patient 
receives may prove to be less effective or to have more side effects than the other study treatment(s) or 
other available treatments. 
There is also a minimal risk of loss of confidentiality.  
In addition to these risks, this research may hurt you in ways that are unknown. These may be a minor 
inconvenience or may be so severe as to cause death. 
 
If you decide to participate in the optional genetic research: 
There is a small risk of health insurance discrimination based on genetic testing; however, per the 
Genetic Information Nondiscrimination Act of 2008 (GINA),  group and individual health insurers may 
not use your genetic information to set insurance eligibility, premiums, or contribution amounts, nor can 
they request or require that you take a genetic test. In addition, employers with 15 or more employees 
may not  use your genetic information to make decisions regarding hiring, firing, job assignments, or 
promotions, nor can they request, require, or purchase your genetic information. In Ohio, there is a 
similar state law that also provides some protection for private health insurance plans. GINA does not 
protect you against genetic discrimination by companies that sell life, disability, or long-term care 
insurance. 
Will being in this study help me in any way? 
If you decide to take part in this research study, there is no guarantee there will be any benefit to you. 
Your condition may become worse or may improve. There may or may not be direct benefit for you 
now, but information from this study may benefit other people now or in the future. The results of this 
study may help us learn if there are potential advantages of utilizing a patient-specific laboratory test 
called batch-selection to decrease the time to success in Immune Tolerance Induction (ITI) for 
hemophilia A patients with inhibitors to FVIII. This research may give rise to new or better treatments. 
What happens to the information collected for the research? 
Efforts will be made to limit use or disclosure of your personal information, including research study 
and medical records, to people who have a need to review this information. We cannot promise 
complete confidentiality. Organizations that may inspect and copy your information include the IRB and 
other University of California representatives responsible for the management or oversight of this study.  
 
Biospecimens (such as blood, tissue, or saliva) collected from you for this study and/or information 
obtained from your biospecimens may be used in this research or other research, and shared with other 
organizations. You will not share in any commercial value or profit derived from the use of your 
biospecimens and/or information obtained from them.” 
 
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P er mi s si o n to T a k e P art i n a H u m a n R e s e ar c h St u d y 
Pa ge 9 of 1 2  
 
F or I R B st a m p  a n d v er si o n d at e o nl y  
 
 
 
 
 
 
I C F Versi o n Date Se pte m ber  7 , 2 0 1 8                                                                                                        D oc u me nt Re visio n Date: Dece m ber  1 2, 2 0 1 8  
 
If y o u recei ve t he M y C u bi x x refri gerat or: A S D H ealt hcare will c ollect de- i de ntifie d data e nt ere d i nt o t he 
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s olel y f or t he res ear c h tea m’s use i n c o n necti o n wit h t he st u d y. 
 
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Dece m ber 2 8, 2 0 1 8
U C Da vis is bei n g p ai d t o c o n d uct t his st u d y. Oct a p har ma U S A, I nc. has p ai d Dr. D uc ore a n d Dr. 
T h or n b ur g, t he pri nci p al i n vesti gat ors, f or t he desi g n a n d c o n d uct of t his st u d y. Dr. D uc ore has a 


Permission to Take Part in a Human Research Study 
Page 10 of 12 
 
For IRB stamp and version date only 
 
 
 
 
 
 
ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
financial interest in Octapharma, the company paying for this study. The sponsor pays Dr. Ducore for 
travel expenses and professional services, such as  speaking engagements and consulting. The income 
that Dr. Ducore receives is in addition to his salary from the University of California. If you have any 
questions, please tell the study coordinators and they will put you in touch with someone to talk to.  
You or your health plan will be billed for the costs of routine medical care you receive during the study. 
These costs may include operating room fees, pharmacy charges, treatments, hospitalization, scans, etc. 
You will be expected to pay for the usual deductibles and co-payments, and for any routine care that is 
not covered. Only the costs of research or experimental procedures will be paid by the study. These 
procedures are the blood draws and laboratory tests for the study.   
For more information about possible costs, please contact the research team. The research team can 
follow UC Davis Uninsured Non-Emergency Estimate Policy (Policy ID 1883) to work with their 
department and Decision Support Services to get you a cost estimate. 
It is important that you promptly tell the person in charge of the research if you believe that you have 
been injured because of taking part in this study. If you are injured as a result of being in this study, the 
University of California will provide necessary medical treatment. Depending on the circumstances, the 
costs of the treatment may be covered by University or the study sponsor or may be billed to your 
insurance company just like other medical costs. The University and the study sponsor do not normally 
provide any other form of compensation for injury.  For more information about compensation, you may 
call the IRB Administration at (916) 703-9151 or email at HS-IRBAdmin@ucdavis.edu. 
You will not be compensated for taking part in this study. 
If you receive the myCubixx refrigerator: In the event your myCubixx device for any reason becomes 
disabled, or you have any issues with the myCubixx device, the research team will provide you with 
initial service support to resolve such issues. If the research team is not able to resolve an issue, the 
research team will notify the Study Coordinating Center at the University of California, Davis. The 
Study Coordinating Center will advise ASD Healthcare of the issue, stating the nature of the issue and 
any known cause, all in a manner that ASD Healthcare will not receive your name, address or other 
identifying information.  If deemed appropriate by ASD Healthcare, they will arrange, through its third 
party affiliate, for the replacement of the myCubixx device.You will not be responsible for any shipping 
costs associated with the replacement if a myCubixx device.  
 
Your Personal Health Information (PHI) will be provided to a ASD Healthcare third party affiliate for 
the delivery of a myCubixx device to your house. Your PHI that will be provided to the third party 
company may include, but is not limited to: your name, address, and telephone number. The third party 
affiliate has agreed that they will not release this indentifiable information. The research team will not 
provide ASD Healthcare with your name, address, or other identifiable information, in connection with 
delivery and return of myCubixx devices.  
 
 
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
988466
December 28, 2018


Permission to Take Part in a Human Research Study 
Page 11 of 12 
 
For IRB stamp and version date only 
 
 
 
 
 
 
ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
Signature Block for Capable Adult 
Your signature documents your permission to take part in this research. 
 
 
 
Signature of subject 
 
Date 
 
 
Printed name of subject 
 
 
 
Signature of person obtaining consent 
 
Date 
 
 
 
Printed name of person obtaining consent 
 
 
 
My signature below documents that the information in the consent document and any other written information was 
accurately explained to, and apparently understood by, the subject, and that consent was freely given by the subject. 
 
 
 
Signature of witness to consent process 
 
Date 
 
 
Printed name of person witnessing consent process 
 
Printed name of person witnessing consent process 
                            Date 
 
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
988466
December 28, 2018


Permission to Take Part in a Human Research Study 
Page 12 of 12 
 
For IRB stamp and version date only 
 
 
 
 
 
 
ICF Version Date September 7, 2018                                                                                                        Document Revision Date: December 12, 2018 
 
Signature Block for Children 
Your signature documents your permission for the named child to take part in this research. 
 
 
Printed name of child 
 
 
 
Signature of parent or individual legally authorized to consent to the 
child’s general medical care 
 
Date 
 
 Parent 
 Individual legally authorized to 
consent to the child’s general 
medical care (See note below) 
Printed name of parent or individual legally authorized to consent to 
the child’s general medical care 
Note: Investigators are to ensure that individuals who are not parents can demonstrate their legal authority to consent to 
the child’s general medical care. Contact legal counsel if any questions arise. 
 
 
 
Signature of parent 
 
Date 
 
 
Printed name of parent 
If signature of second parent not obtained, indicate why: (select one) 
 The IRB determined that the permission of one parent is 
sufficient.  
 Second parent is deceased 
 Second parent is unknown  
 Second parent is incompetent 
 Second parent is not reasonably available 
 Only one parent has legal responsibility for the care 
and custody of the child 
 
Assent 
 Obtained 
 Not obtained because the capability of the child is so limited that the child cannot reasonably be consulted. 
 Waived by the IRB because the intervention or procedure involved in the research holds out a prospect of direct 
benefit that is important to the health or well-being of the child and is available only in the context of the 
research. 
  
 
 
 
Signature of person obtaining consent and assent 
 
Date 
 
 
 
Printed name of person obtaining consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPROVED by the Institutional Review
Board at the University of California, Davis
Protocol
APPROVED
988466
December 28, 2018