Clinical trial NCT04303559
Conditions: Hemophilia A Without Inhibitor
Keywords: hemophilia A eloctate Emicizumab inhibitor
Sponsor: Margaret Ragni
Start date: 2021-10-11; Completion date: 2022-06-16
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center randomized phase III clinical trial, the Inhibitor Prevention Trial, in which Eloctate will be compared with Emicizumab, using adaptive design, to prevent inhibitors in patients with severe hemophilia A.

Detailed description:
This is a multi-center randomized phase III clinical trial, the Inhibitor Prevention Trial, in which consecutive hemostatic agents will be compared using adaptive design to prevent inhibitors in patients with severe hemophilia A. This adaptive design is necessary as randomized trials in rare diseases are otherwise not possible. This adaptive design is necessary as randomized trials in rare diseases are otherwise not possible. The INHIBIT Clinical Trials Platform includes two linked trials, the Inhibitor Prevention Trial (Prevention Trial) and the Inhibitor Eradication Trial (Eradication Trial) that will be conducted at up to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. The Inhibitor Prevention Trial is a 48-week randomized phase III trial, in which 66 previously untreated patients (PUPs) with severe hemophilia A will be enrolled. Subjects will include children from 4 months of age up to 4 years of age who have not been previously treated with clotting factor. Once enrolled, subjects who meet all the inclusion and none of the exclusion criteria will be randomized to preemptive weekly Eloctate (rFVIIIFc) vs. weekly Emicizumab (Hemlibra) to prevent inhibitor formation, defined as anti-FVIII \>= 0.6 BU. Blood draws will be minimized to 6 timepoints, pre, 4, 12, 24, 36, and 48 weeks, and validated for small volumes, 3.8 cc (¾ tsp) each. The Inhibitor Prevention Trial is considered greater than minimal risk as study drug is given before the first bleed and special inhibitor studies are obtained. (NB: The Inhibitor Prevention Trial (PRO19040140) is linked to the Inhibitor Eradication Trial (PRO19070080), as part of the INHIBIT Clinical Trials Platform, with both trials will be conducted efficiently in the same hemophilia treatment centers (HTCs), with the same MDs, coordinators, visit frequency, blood sampling, and assays.

Arms: arm 1: Arm A: Eloctate 65 IU/kg will be administered weekly by intravenous infusion in previously untreated children with severe hemophilia A beginning before the first bleed and continued up to 48 weeks. arm 2: Arm B: Emicizumab 1.5 mg/kg will be administered weekly by subcutaneous injection (following 3 mg/kg/wk x4 induction) in previously untreated children with severe hemophilia A beginning before the first bleed and continue up to 48 weeks.
Interventions: intervention 1: Eloctate Injectable Product intervention 2: Emicizumab Injection [Hemlibra]
Intervention descriptions: intervention 1: This is a factor VIII-Fc fusion protein. intervention 2: This is a bispecific monoclonal antibody FVIII mimic.

Protocol documents:
Prot_SAP_001.pdf: 
1 
Phase III Multicenter, Randomized Controlled 
Inhibitor Prevention Trial, Comparing      
Eloctate (rFVIIIFc) and Emicizumab (Hemlibra) 
to Prevent Inhibitor Formation           
in Severe Hemophilia A:       
The Inhibitor Prevention Trial 
Short Title:  The INHIBIT Prevention Trial 
Protocol Number: PRO19040140 
National Clinical Trial (NCT) Identified Number: NCT04303559 
Principal Investigator: Margaret V. Ragni, MD, MPH 
Co-investigators: Marnie Bertolet, PhD, and Maria Mori Brooks, PhD 
Funded by: HRSA H30MC24050 
Version Number:  v3.0 
08-June 2021


 
 
 
 
 
 
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PROTOCOL SUMMARY 
Title:    
The Inhibitor Prevention Trial (PREVENT): A Phase III Multicenter, Randomized, Controlled Trial, 
comparing Eloctate (rFVIIIFc) vs. Emicizumab (Hemlibra) to Prevent Inhibitor Formation in Severe 
Hemophilia A.  
Study Description: 
This is a prospective, multicenter randomized phase III 48-week clinical trial comparing rFVIIIFc 
(Eloctate (Eloctate®) vs. Emicizumab (Hemlibra®) in severe hemophilia A patients. Subjects will 
include previously untreated male children with severe hemophilia A (FVIII < 0.01 U/ml). We 
hypothesize that preemptive weekly prophylaxis with Emicizumab is non-inferior to Eloctate 
begun before the first bleed (excluding circumcision), in reducing or preventing inhibitor 
formation in children 4 months to 4 years of age with severe hemophilia A. 
Objective: 
The Primary Objective is to determine if Emicizumab is no worse than Eloctate in preventing 
inhibitor formation in previously untreated patients (PUPs) with severe hemophilia A, with no 
more than 3 exposures to FVIII (FVIII, cryo, FFP) including circumcision, and no detectable 
inhibitor, anti-FVIII < 0.6 B.U. 
The Secondary Objectives are to evaluate the safety and mechanism of Eloctate vs. Emicizumab 
prophylaxis in preventing inhibitor eradication. 
 
Endpoints: 
The Primary Endpoint is inhibitor development, defined as the development of anti-FVIII > 0.6 
B.U. The anti-FVIII will be repeated will be repeated on the sample immediately, and a second 
sample obtained within 4 weeks to confirm the result. The Secondary Endpoints include a) safety 
by bleeding, measured by the number and frequency of bleeding episodes (i.e. hematoma, joint, 
CNS bleed), and time to port infections; and b) mechanism of inhibitor suppression (prevention) 
by FVIII-specific T cell ELISPOT, B cell, Ig, and RNA assays and cytokine assays to determine the 
role of T regs in controlling immune response to FVIII; and by FVIII genotype; HLA type; and 
chromogenic FVIII trough levels; and by microbiome stool sample, each compared with anti-FVIII. 
Study Population: 
Study subjects will be male children age > 4 months to 4 years of age with severe hemophilia A, 
defined as factor VIII < 0.01 IU/ml, with no more than 3 FVIII exposures (FVIII concentrate, 
cryoprecipitate, or FFP) including for circumcision. A total of 66 eligible subjects with severe 
hemophilia A will be enrolled in this 6-year trial. 
Site Enrolling Subjects:  Up to 41 Participating Hemophilia Treatment Center (HTCs).   
Description of Study 
There are two study interventions: Eloctate vs. Emicizumab.  
Intervention: 
Recombinant factor VIII Fc (Eloctate®) is an FDA-approved clotting factor approved for treatment 
and/or prevention of bleeds in hemophilia A. It is an intravenous agent supplied as single-use vials 
containing approximately 250, 500, 750 IU per vial. The vials are reconstituted with 5-10 ml vial 
of sterile water for injection, USP, which is transferred by two-way needle into the lyophilized 
powder for reconstitution, and the reconstituted vial infused over 5-10 minutes, at 65 IU/kg once 
weekly for 48 weeks. 
Emicizumab (Hemlibra®) is an FDA-approved agent for the prevention of bleeding in hemophilia 
A. It is a subcutaneous agent supplied in vial sizes of approximately 30 mg per ml, 60 mg per 0.4 
ml, and 105 mg per 0.7 ml. A tuberculin syringe allows transfer of the drug from the vial for 
subcutaneous injection over 1-2 minutes, at 1.5 mg/kg weekly, following a 4-week induction with 
3.0 mg/kg/week.  
 
Trial Arms 
 Arm A 
Eloctate 65 IU/kg IV weekly for 48 weeks 
 Arm B 
Emicizumab 1.5 mg/kg SQ weekly (after 3.0 mg/kg/wk x 4 wk induction) for 48 weeks 
         
Study Duration: 
This is a 48-week outpatient trial in which all subjects will be randomized to one of two treatment 
arms and followed for 48 weeks. 
 


 
 
 
 
 
 
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Abstract 
 
     
     This is a multi-center randomized phase III clinical trial, the Inhibitor Prevention Trial, in which Eloctate (rFVIII-Fc) will 
be compared with Emicizumab (Hemlibra) using Bayesian platform design to prevent inhibitors in patients with severe 
hemophilia A. This design is necessary as randomized trials in rare diseases are often not possible. The INHIBIT Clinical 
Trials Platform includes two linked trials, the Inhibitor Prevention Trial (Prevention Trial) and the Inhibitor Eradication Trial 
(Eradication Trial) that will be conducted at up to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. 
The Inhibitor Prevention Trial is a 48-week randomized phase III trial, in which 66 previously untreated patients (PUPs) 
with severe hemophilia A will be enrolled. Subjects will include children from 4 months of age up to 4 years of age who 
have not been previously treated with clotting factor. Once enrolled, subjects who meet all the inclusion and none of the 
exclusion criteria will be randomized to preemptive weekly Eloctate (rFVIIIFc) vs. weekly Emicizumab (Hemlibra) to prevent 
inhibitor formation, defined as anti-FVIII > 0.6 BU. Blood draws will be minimized to 6 timepoints, baseline, 4, 12, 24, 36, 
and 48 weeks post-randomization, and validated for small volumes, 3.8 cc (¾ tsp) each. The Inhibitor Prevention Trial is 
considered greater than minimal risk as study drug is given before the first bleed and special inhibitor studies are obtained. 
(NB: The Inhibitor Prevention Trial (PRO19040140) is linked to the Inhibitor Eradication Trial (PRO19070080), as part of 
the INHIBIT Clinical Trials Platform, with both trials will be conducted efficiently in the same hemophilia treatment centers 
(HTCs), with the same MDs, coordinators, visit frequency, blood sampling, and assays.  
 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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Principal Investigator:  Margaret V. Ragni, MD, MPH   
 
Protocol Title: The Phase III Multicenter, Randomized, Controlled Inhibitor Prevention Trial, comparing Eloctate 
(rFVIIIFc) vs. Emicizumab (Hemlibra) to Prevent Inhibitor Formation in Severe Hemophilia A. 
 
1.0 
Objective and Specific Aims 
The purpose of the Inhibitor Prevention Trial is to prevent inhibitor formation in children with severe hemophilia A. This 
48-week phase III open-label, randomized, controlled trial, compares the recombinant factor VIII Fc fusion protein Eloctate 
(rFVIIIFc) vs. the bispecific monoclonal antibody FVIII mimic Emicizumab (Hemlibra), each given as weekly preemptive 
prophylaxis, to prevent inhibitor formation in children with severe hemophilia A. Eloctate is approved by the FDA to 
prevent and treat bleeds in children and adults with hemophilia A; while Emicizumab is approved by the FDA to prevent 
bleeds in children and adults with hemophilia A with and without inhibitors. In this trial, Eloctate and Emicizumab will be 
assessed in the prevention of inhibitor formation in children with severe hemophilia A who are previously untreated 
patients (PUPs). The research in this trial is considered greater than minimal risk as it involves initiating weekly dosing 
before the first bleed and obtaining special inhibitor studies. The primary efficacy endpoint will probability of inhibitor 
development by 48 weeks, defined as anti-FVIII > 0.6 B.U. by chromogenic Nijmegen Bethesda assay (CBA), repeated 
immediately and confirmed within 4 weeks. Secondary endpoints will include a) safety, measured by frequency of bleeds 
(hematomas, joint, CNS bleeds), and b) mechanism of inhibitor prevention, measured by FVIII-specific T cell ELISPOT assay, 
performed on peripheral blood mononuclear cells (PBMC) at baseline and at 4, 12, 24, 36, and 48 weeks. The B cell, Ig, 
and RNA assays will be performed on an aliquot of PBMCs. Studies will be performed on T cell populations depleted of 
regulatory T cells (T reg) (CD4+CD25+FoxP3+) to determine the role of T regs in controlling immune response to FVIII. 
Hemophilia genotype and HLA assays will be determined at baseline on the buffy coat of plasma. A microbiome (stool 
sample) will be obtained at baseline. The trial will assess inhibitor formation after each subject completes the 48-week 
trial. The Inhibitor Prevention Trial is designed to test whether Emicizumab is non-inferior or superior to Eloctate in 
preventing inhibitor formation by 48 weeks. At the interim, once 75% of subjects are randomized, the Bayesian posterior 
probability that the Emicizumab arm is more likely to prevent inhibitor formation than the Eloctate arm must be at least 
99% to stop the trial. Assuming the trial does not stop at the interim to declare non-inferiority at the end of the trial, the 
Bayesian posterior probability that Emicizumab is non-inferior to Eloctate in preventing inhibitor formation must be at 
least 95.7%. If non-inferiority is met, then to declare Emicizumab superior to Eloctate at the end of the trial, the Bayesian 
posterior probability that the Emicizumab arm is more likely to prevent inhibitor formation than the Eloctate arm must be 
at least 95.1%. This maintains type 1 error at 5%, one-sided, with 85% power for non-inferiority and 28% power for 
superiority if we assume that the true condition is that Emicizumab is 10% superior to Eloctate (85% vs. 75% inhibitor-
free). 
 
2.0 
Background and Significance 
2.1     
Background 
          
Hemophilia A is an X-linked inherited bleeding disorder caused by deficient or defective coagulation factor VIII 
(FVIII) that affects approximately 20,000 in the U.S. and 80,000 worldwide. It is characterized by spontaneous and 
traumatic bleeding into joints, soft tissue, and muscles. Among the most severe complications of hemophilia treatment is 
the formation of inhibitor alloantibodies directed against exogenous factor VIII which occurs in up to 30% or more of 
hemophilia patients. Inhibitor formation is a T cell-dependent B-cell immune response, which was first recognized in HIV(+) 
hemophilia inhibitor patients whose inhibitors disappeared when CD4+ T cells fell below 200/µl and re-appeared after HIV 
antiviral therapy restoration of CD4 cells to >200/ µl. Inhibitor formation typically occurs early in life, after a median of 10-
20 exposure days. Inhibitors bind to exogenous FVIII, neutralize its activity, interfering with clinical hemostasis and, despite 
bypass therapy (e.g. rFVIIa or factor IX concentrates) often leads to uncontrolled bleeding and increased morbidity, cost, 
hospitalization. Thus, inhibitors are a major cause of morbidity and high healthcare cost. CDC studies have determined 
inhibitor patients are twice as likely to require hospitalization for bleeding complications and cost on average ten times 
more than hemophilia patients without inhibitors.  
         Medical management of individuals with inhibitors is difficult. The use of bypass agents, including the response of 
inhibitor patients to alternative or bypass agents, such as factor rVIIa or activated IX, which is somewhat unpredictable 
and suboptimal, and morbidity is high as are healthcare costs. For over 30 years, the only approach to eradication of 


 
 
 
 
 
 
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inhibitors has been immune tolerance induction therapy (ITI), a program of regular FVIII infusions over a prolonged period 
of time, which is inconvenient, expensive, and effective in only 75-80% of those treated. Thus, a major goal of 
comprehensive hemophilia care is to prevent inhibitors before they occur, incorporating potentially more effective 
therapies, such as the novel therapies in development and FDA-approved, e.g. Eloctate and Emicizumab, to promote 
better outcomes in those with hemophilia. 
Among those who develop inhibitors, 50% do so within the first 20 factor VIII exposures, and over 95% within the 
first 50 factor VIII exposures, suggesting there may be a potential window of opportunity to intervene to prevent inhibitor 
formation. To date, however, it has been difficult to identify those at risk who might benefit from inhibitor prevention 
efforts. Risk factors for inhibitor formation are well established, including patient-related (genetic) factors such as race 
(African American), family history, and genotype (large deletion mutations); and treatment-related (environmental) 
factors, especially high-intensity factor exposure at an early age. Despite this information and recently developed scoring 
systems, it has been difficult to identify those at risk early enough to target prevention efforts.  
Equipoise: We are in a state of equipoise as the optimal approach to prevent inhibitor formation in hemophilia is 
not known. Studies of children with hemophilia have determined that when the first treatment with factor VIII (first 
“exposure”) is for a severe bleed, surgery, or trauma, an inhibitor is more likely to form than when the first treatment is 
for prevention of a bleed. This is thought to be because severe bleeds, surgery, or trauma may trigger the immune system 
to make an antibody to any foreign protein, and the first factor VIII exposure occurs during a severe bleed, surgery, or 
trauma, the immune system may identify it as a “foreign” protein or threat (“danger”) and make an antibody (“inhibitor”) 
against it. This is called the “danger” theory (Matzinger). Yet, avoiding danger is not sufficient to prevent inhibitor 
formation as shown in previous studies of previously untreated children (PUPs) receiving rFVIII.  
 Eloctate (rFVIIIFc) is an FDA-approved FVIII protein that “fuses” recombinant FVIII (rFVIII) to IgG (globulin protein), 
prolongs FVIII half-life in the circulation. In human clinical trials, Eloctate provides longer protection against bleeds than 
standard rFVIII via a longer half-life than rFVIII. Further, Fc has been shown to induce tolerance to the hapten to which it 
is fused, in this case rFVIII: specifically, Eloctate induces regulatory T cells (T regs) which promotes tolerance to rFVIII. In 
hemophilia A mice receiving weekly Eloctate, the rate of inhibitor formation was significantly lower than in mice given 
standard factor VIII, i.e. full length rFVIII (Advate) or B-domain deleted rFVIII (Xyntha) (Liu). In clinical trials, while Eloctate 
is safe and effective in adults, adolescents, and children (Powell), inhibitors still develop in ~25% of 89 previously untreated 
patients (PUPs) receiving Eloctate prophylaxis (A-LONG trial), similar to prospective studies in rFVIII-treated PUPs, 28-30% 
(Gouw). To date there has been no randomized comparison between these agents, in part because this is a rare population 
and there is waning interest in use of rFVIII in young children because it requires three infusions per week. Taken together, 
these findings suggest the potential utility of an inhibitor prevention approach that employs a once weekly infusion that 
avoids initial factor exposure at the time of a bleed (“danger”) by avoiding bleeds/ surgery/ trauma, and potentially 
promotes FVIII tolerance.    
Emicizumab (Hemlibra) is an FDA-approved bispecific monoclonal antibody that has been shown to be safe and 
effective in phase III trials in hemophilia A with (Oldenburg) or without inhibitors (Mahlangu) and is increasingly being 
used because of its simpler subcutaneous route. Whether Emicizumab may reduce inhibitor formation by avoiding FVIII 
exposure in the vulnerable first 50 exposure days in PUPs is not known; however, breakthrough bleeds (hematomas, 
hemarthroses) during Emicizumab prophylaxis that requiring FVIII may increase “danger” and potential inhibitor 
formation, and potentially negating its potential benefit. 
For these reasons, we will study if Emicizumab is noninferior to Eloctate in preventing inhibitor formation in PUPs 
when begun before FVIII given for a bleed or surgery or trauma (preemptive) and continued weekly to prevent bleeds 
(prophylaxis). We hypothesize that avoiding danger, prolonging FVIII half-life, and promoting T reg tolerance will reduce 
or prevent inhibitor formation. The concept of initiating Eloctate in children before they have a bleed is innovative, as it 
advances the “avoidance of danger” concept. Dosing once weekly addresses the greatest drawback to current prophylaxis 
regimens requiring 3-4 times weekly infusion for prophylaxis in children, namely difficult access and need for central lines 
or ports. The concept of avoiding FVIII exposure during the vulnerable first 50 exposure days by the non-factor hemostatic 
agent, Emicizumab, may be important in reducing inhibitor formation, and its effectiveness in preventing bleeds in 
hemophilia with or without inhibitors makes it a potentially powerful agent in the management of hemophilia: yet, the 
potential for breakthrough bleeds may complicate its potential use. 


 
 
 
 
 
 
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Specific Aim 1: To compare weekly Emicizumab and Eloctate in preventing anti-FVIII inhibitor formation when 
each is initiated before the first bleed in previously untreated children (PUPs) with severe hemophilia A in the Prevention 
Trial. We will conduct this multi-center, randomized phase III clinical trial at 31 (up to 40) HTC sites, with the same study 
visit frequency, blood sampling, and lab assays as in the companion Eradication Trial (PRO19070080). The primary 
endpoint is the development of anti-FVIII antibody > 0.6 BU by chromogenic Nijmegen-modified Bethesda assay (CBA) by 
48 weeks.   
Hypothesis 1: We hypothesize that Emicizumab is non-inferior to Eloctate in preventing inhibitors, anti-FVIII > 0.6 
B.U. (CBA), in children with severe hemophilia A, when each is given weekly for 48 weeks, beginning before the first bleed, 
in the absence of “danger.” Yet, there is equipoise, as Eloctate induces Tregs and promotes FVIII tolerance and may be 
superior to Emicizumab in inhibitor prevention; but as Emicizumab avoids FVIII exposure, it may be superior to Eloctate, 
unless breakthrough bleeds occur that require FVIII, i.e. “danger,” and trigger an immune activation and inhibitor 
formation, making Emicizumab inferior to Eloctate. However, as Emicizumab is given subcutaneously, if it were non-
inferior to Eloctate in reducing inhibitors, it would be the “winner” over Eloctate.  
 Specific Aim 2: To evaluate the safety and mechanism of inhibitor prevention in patients with severe hemophilia 
A. Secondary endpoints include a) safety, measured by number and frequency of bleeding episodes (i.e. hematomas, 
hemarthroses) and port infections; and b) mechanism of inhibitor prevention, measured by FVIII-specific T cell ELISPOT 
assay; FVIII genotype; HLA type; and chromogenic FVIII trough levels; and by microbiome stool sample, each compared 
with anti-FVIII. 
Hypothesis 2: We hypothesize that safety, measured by bleeds requiring rescue factor or prophylaxis escalation, 
and port infections, will not differ between treatment arms; and the mechanism by which Eloctate suppresses (prevents, 
eradicates) inhibitor formation is via Fc induction of regulatory T cells (Tregs) promoting FVIII tolerance, measured by 
ELISPOT assay. This novel approach to prevent inhibitor formation is compelling, and, if successful, will eliminate a major 
complication of hemophilia treatment and the associated morbidity, hospitalization, cost, and early mortality, and be 
adopted immediately into clinical practice. 
 
The Inhibitor Prevention trial is a 48-week outpatient trial conducted in 66 PUPs from up to 41+ Hemophilia 
Treatment Centers (HTCs) (1-4 subjects locally). Case report forms and laboratory assessment forms will be completed 
and uploaded to a web-based database. While a landmark study established three times weekly prophylaxis as standard 
prophylaxis dosing, based on reduction in joint bleeds and improved joint range of motion, only 46% of surveyed HTC 
physicians initiate prophylaxis at this dose and frequency. In fact, 32% prescribe once-weekly prophylaxis, with escalation 
for break-through bleeds, similar to the published Canadian experience (Feldman), thereby avoiding invasive central lines 
and attendant infection risk. Although inhibitor frequency was lower, 8%, with the latter approach, the frequency of joint 
bleeds was higher, 19.6% vs. 12.5% at 6 months. Further, most centers wait to initiate prophylaxis until after the first 
bleed. A survey of HTCs physicians indicates that 54% of physicians use a once- or twice-weekly prophylaxis regimen in 
young children, beginning after the first bleed (Ragni). Despite these small studies, effective inhibitor prevention remains 
a compelling problem for which an effective approach would be practice changing.  
 
2.2   Significance: Inhibitor formation is the most serious complication of hemophilia, affecting 25-30% of those with 
severe hemophilia A. Inhibitor formation is a T cell-dependent B-cell response to exogenous FVIII that renders lifesaving 
factor treatment ineffective and leads to poorly controlled bleeding, severe morbidity, frequent hospitalizations, and high 
healthcare costs. Thus, preventing inhibitors before they occur would promote better health outcomes for children and 
adults with hemophilia, an approach that would be adopted immediately into clinical practice. The drugs we will study are 
FDA-approved and safe and effective in preventing bleeds in adults and children with hemophilia A, and preliminary data 
from small studies support the need for clinical trials to determine optimal use of these agents to prevent inhibitor 
formation in severe hemophilia A. The Inhibitor Prevention Trial is innovative as it uses a Bayesian platform design to 
compare novel agents in a randomized phase III trial. The trial will incorporate historical data on inhibitor formation 
(Bayesian priors), which allows for more efficient use of rare subjects and improved power. Subjects from the Prevention 
Trial who develop inhibitors, along with pre-existing refractory inhibitor patients at the same HTCs, can be enrolled in the 
Eradication Trial (PRO 19070080) to compare immune tolerance induction with single or combination novel agents. The 
two trials are integrated for efficiency and conducted at the same HTCs, with the same visit frequency, blood draws, and 
lab assays. Moreover, as promising new agents emerge, they could potentially be incorporated into the trial platform 


 
 
 
 
 
 
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design. Finally, the findings of this trial will potentially provide new information on prevention of a major complication of 
hemophilia and promote blood product safety, per the goals of Healthy People 2020. 
 
3.0 
Research Design and Methods 
3.1    
Drug/Device Information  
         
Eloctate (rFVIIIFc) and Emicizumab (hemlibra) are FDA-approved for the prevention and/or treatment of bleeds in 
hemophilia A, and are safe and effective in adults, adolescents, and children. For this trial, subjects will use their own 
supply of study drug to which they are randomized. Clinical trials of Eloctate and Emicizumab in adults and children with 
severe hemophilia A have demonstrated safety and efficacy when used to prevent bleeds or promote hemostasis in 
surgery. In this trial, subjects will use Eloctate or Emicizumab to prevent bleeds, which is within the current standard of 
care guidelines in which clotting factor is begun before or after 1-2 bleeds, per physician discretion, to prevent bleeds 
(prophylaxis). Subjects will maintain a home inventory of the study drug(s) to which they are randomized. Eloctate in vial 
sizes of approximately 250, 500, and 750 is available for children: a two-way needle will allow transfer of the diluent into 
the lyophilized powder for reconstitution and slow infusion over 5-10 minutes. Emicizumab in vial sizes of approximately 
30 mg per ml, 60 mg per 0.4 ml and 105 mg per 0.7 ml is available for children: a tuberculin syringe will allow transfer of 
the drug from the vial for injection over 1-2 minutes. The study drugs will be available by physician prescription which can 
be filled at the HTC pharmacy or at another pharmacy of the patient’s or parent/caretaker’s choice.  
           Once a subject is consented and identified as eligible for the trial, a unique subject number will be assigned to each 
subject by the Data Coordinating Center (DCC), Graduate School of Public Health (GSPH), University of Pittsburgh, 
Pittsburgh, PA. Study drug dosing will be given by the hemophilia center nurse, clinic or hospital infusion center, or, if on 
home treatment, by parent, care provider, or visiting nurse, in the usual manner: this is either by intravenous infusion 
(Eloctate) over 5-10 minutes through a winged infusion needle (butterfly) heplock placed in the forearm, or, if required, a 
central line; or by subcutaneous injection (Emiczumab) over 1-2 minutes with a tuberculin syringe in the abdomen or 
thigh. This study site will maintain accurate records, including dates, times, and doses administered, and families will 
maintain a diary to record the same information. 
 
3.2   Research Design  
        This is a 48-week outpatient, randomized phase III clinical trial, that employs a Bayesian platform design to conduct 
the Prevention Trial in patients with severe hemophilia A, FVIII < 0.01 IU/ml. Because hemophilia is a rare disease, we 
incorporated Bayesian platform design and will use historical and prospective ongoing clinical trial data on inhibitor 
formation (Bayesian “priors”) to efficiently use rare patients and increase power. The Inhibitor Prevention Trial is linked 
to the Inhibitor Eradication Trial, and the trials are integrated so there is efficiency and economy, using the same HTCs, 
staff, frequency of blood sampling, visits, data collection, and lab assays. The Prevention Trial is a randomized phase III 
open-label trial designed to evaluate the efficacy of preemptive weekly prophylaxis with Eloctate vs. Emicizumab to 
prevent inhibitor formation in children > 4 months of age up to 4 years with severe hemophilia A. Approximately 1-4 
previously untreated children with severe hemophilia will be recruited at each HTC. The study drugs will be initiated prior 
to the first bleed and administered to each subject for up to 48 weeks. Eloctate will be given by weekly intravenous infusion 
of 65 IU/kg by weekly intravenous infusion over 5-10 minutes. Emicizumab will be given weekly subcutaneous injection of 
1.5 mg/kg SQ weekly (after a 4-week induction at 3.0 mg/kg/wk x 4 weeks) over 1-2 minutes. For treatment of 
breakthrough bleeds, for safety reasons, additional Eloctate doses will be given, after which study drug dosing will be 
continued at least weekly and escalated per physician discretion, as is standard of care per a recent HTC survey. The 
treating physician may be the study physician. All bleeds and study drug(s) will be recorded by patient or parent/ caretaker 
for each subject in a patient diary. All randomized subjects will be followed 48 weeks or until they reach the study outcome 
of inhibitor formation. Follow-up visits will be monthly until end-of-study, week 48.  
         The Data Safety Monitoring Board (DSMB) will be responsible for reviewing all data generated for the study 
interventions, from the time of dosing through the end of each 48-week trial. Each study will consist of three phases; a 
Screening Period, a Treatment Period, and a Post-Treatment Period. 
         Screening Period: Subject eligibility for the study will be determined prior to study drug dosing. A history of past 
bleeds, factor treatment, and circumcision bleeding and treatment will be obtained. A baseline blood sample will be 
collected for anti-FVIII inhibitor titer by chromogenic Nijmegen Bethesda assay (CBA), FVIII-specific T cell (ELISPOT), trough 


 
 
 
 
 
 
 8 
FVIII (chromogenic assay), HLA, hemophilia genotype, and sample storage for future testing. A microbiome stool sample 
will also be obtained. A baseline height, weight and brief physical exam will be obtained.  
         Treatment Period: After random assignment to one of two treatment regimens, the treatment period will extend for 
up to 48 weeks, beginning with weekly Eloctate or Emicizumab prophylaxis begun before the first bleed. If a break-through 
bleed occurs during the trial, Eloctate will be given per standard of care to all subjects: in those on the Eloctate arm, this 
may lead to escalation of the dose from once to twice weekly as in typical practice, per physician discretion; whereas in 
subjects on the Emicizumab arm, Emicizumab dosing remains unchanged as it is not a treatment but rather a prophylaxis 
to prevent bleeds. If a subject develops an inhibitor, either Eloctate (65 IU/kg), in the case of a low-responding inhibitor, 
or rFVIIa (90 µg/kg), in the case of a high-responding inhibitor, will be used to treat bleeds, at physician discretion. NOTE: 
FEIBA (factor VIII inhibitor bypass activity) will not be allowed on these trials as it may result in thrombosis or thrombotic 
microangiopathy in patients taking Emicizumab.  
The frequency and number of new (developing) inhibitors will be analyzed in subjects by assigned treatment during the 
study; if a subject receives another clotting protein for any reason, he will be monitored and followed to 48 weeks and 
included in the primary intention-to-treat analysis. All bleeds and factor use will be recorded in a patient diary. Height, 
weight, and a brief physical exam will be performed every month at routine study visits, and factor supply reviewed for 
each study subject, and, if necessary, reordered at that visit. Laboratory assays including anti-FVIII inhibitor by 
chromogenic Nijmegen modified Bethesda assay CBA), antigen-specific T cell assays (ELISPOT), hemophilia genotype, 
trough FVIII (chromogenic assay), and sample storage for future studies will be obtained at baseline and at week 4, 12, 24, 
36, and 48. Hemophilia genotype and HLA will be performed at baseline only. All samples must be drawn before the study 
drug dose.  
         Post-Treatment Period: The post-treatment period begins after the last day of study follow-up at week 48 or when 
the subject develops an inhibitor.  All clinical and lab data will be reviewed and entered on the INHIBIT Trial DCC Data 
Management System website through the end of the entire study period.  
 
This is a randomized Phase III Clinical Trials Platform that includes 2 phase III randomized controlled clinical trials, the 
Prevention Trial (PRO1904140) and the Eradication Trial (PRO19070800) in severe hemophilia A which utilize the same 
HTCs, sampling time, volume, and frequency, visits, and lab assays to enhance trials efficiency. In the Prevention Trial, all 
subjects will be enrolled before no more than 3 FVIII exposures (FVIII in concentrate, cryoprecipitate, or FFP) including 
circumcision. Subjects will be randomized to receive weekly Eloctate 65 IU/kg or weekly Emicizumab 1.5 mg/kg (after 
standard 3.0 mg/kg/wk x4 wk induction) beginning before the first bleed. The doses of these drugs are consistent with 
standard of care guidelines for bleed prevention (prophylaxis) per physician discretion. Subjects will receive the drug to 
which they are randomized weekly, preferably between 7 am and 9 am, beginning before a bleed and continued weekly 
through study week 48. All bleeds and factor use will be recorded in the Subject Diary. This is an open-label trial, so subjects 
enrolled on the study will receive study drug by physician prescription. Baseline variables, all potential risk factors, 
including age, family history of inhibitors, race, and circumcision, will be collected prior to randomization and prior to 
initiating study drug. (NB: Circumcision is performed in over 50% of hemophilic children in the U.S. and is not an 
established risk for inhibitor formation). 
 
Bleeding Episodes Occurring during Study 
     For breakthrough bleeds occurring during the study, Eloctate 65 IU/kg will be the treatment of choice, and escalated, 
per physician discretion, from once weekly to twice weekly or three times weekly prophylaxis for bleeds. In subjects who 
develop an inhibitor (anti-FVIII > 0.6 BU), once confirmed, treatment will be based on the type inhibitor: in those 
developing a low-responding inhibitor (defined as no inhibitor increase after FVIII dosing), Eloctate is the treatment of 
choice for breakthrough bleeds; however, for those unresponsive to Eloctate, or for those who develop a high-responding 
inhibitor (defined as inhibitor increase, i.e. anamnestic response, after FVIII dosing), rFVIIa 90 mcg/kg will be the treatment 
of choice for breakthrough bleeds, per physician discretion. The HTC coordinator will review study drug(s) supply with the 
parent/ caretaker to assure it is re-ordered when three doses are left. There will be no change in study visits. 
 
 
 


 
 
 
 
 
 
 9 
Subjects Developing the Primary Endpoint 
 
     The primary endpoint will be development of an inhibitor, defined as anti-FVIII > 0.6 B.U. (chromogenic Nijmegen 
Bethesda assay, CNA). A local lab anti-FVIII > 0.6 B.U. will be repeated on this sample or, if insufficient, a repeat sample 
within 7 days, and a second sample obtained within 4 weeks for confirmation. A central lab anti-FVIII > 0.6 B.U. will be 
repeated within 4 weeks for confirmation. All subjects developing inhibitors will remain on study follow-up to week 48. At 
the time an inhibitor is detected, the subject’s treating physician (who may be the study physician) is encouraged to obtain 
an inhibitor test locally, if possible. The treatment approach will be at physician discretion: once the anti-FVIII is confirmed 
positive, subjects will be able to enroll on the Eradicate Trial, or receive, at physician discretion, immune tolerance 
induction (ITI) with Eloctate or other FVIII product, to suppress the inhibitor; and rFVIIa for bleeds. FEIBA will not be 
allowed on this trial for safety reasons.  
It is anticipated that 1-4 subjects will be enrolled locally, contributing to the overall study enrollment of 66 subjects at one 
of up to 41+ participating HTCs (hemophilia treatment centers). The duration of the study is approximately 48 weeks per 
subject, with an expectation the study will last up to 7 or more years, subject to enrollment and completion of all 
procedures. For this study, all study visits will occur at the HTC. 
SCREENING VISIT, RANDOMIZATION, AND INITIATION OF ASSIGNED TREATMENT 
Study Visit 1, Screening/ Baseline Visit, Wk 0                                                                                                                 
This visit will take place prior to administration of Eloctate or Emicizumab in order to confirm eligibility requirements. 
Randomization and initiation of treatment may occur at this visit or within 4 weeks of the visit. The following tests or 
assessment will be performed at the Screening/ Baseline Visit.  
• 
Study physicians will discuss the study with the patient or parent/caretaker of potential study subjects, answer 
questions and assure there is adequate time for the parent/caretaker to decide if their child will participate in the 
study. The patient or parent/caretaker may sign the consent or take the consent with them to discuss with family 
members and/or other members of their healthcare team. If the parent/ caretaker is interested in the child 
participating in the study, they may sign the consent and the child will be enrolled in the trial. No study 
procedures will occur until after the parent/care giver has signed the consent document. 
• 
Subjects currently receiving Emicizumab will be asked to discontinue the medication prior to randomization. If the 
subject or parent/caretaker is not willing to discontinue treatment, they will be deemed ineligible. If a subject 
discontinues Emicizumab prior to randomization, there is no need for a washout period and there are no known 
risks of stopping Emicizumab. If a bleed occurs, factor VIII (FVIII) will be given per physician discretion until it 
resolves and monitored by home treatment records, per standard of care.   
• 
Demographics of the subject will include age, date of birth, race, and hemophilia genotype, if known. 
• 
Other medical and surgical history of the subject will include height, weight, past bleeds, circumcision, and past 
factor treatment, dose and frequency. 
• 
Hemophilia diagnosis by history, with historical laboratory test result for confirmation. 
• 
Medication history including all concomitant medications within 4 weeks of the first dose of study drug. 
• 
Brief physical exam including vital signs, height (cm) and weight (kg).   
• 
Blood draw: A 3.8 ml (¾ tsp) blood sample will be collected for anti-FVIII chromogenic Nijmegen Bethesda(CBA) 
assay (plasma), antigen-specific (FVIII) T cell ELISPOT assay (PBMC), HLA and hemophilia genotype (buffy coat of 
the plasma sample), trough FVIII chromogenic activity (aliquot of plasma), and a sample (plasma) stored for future 
studies. All samples must be drawn prior to the study drug dose. Amounts of blood drawn will be less for children 
weighing less than 14 pounds. The Appendix detailing timing of visits and blood draws is attached on the last page 
of this protocol.  
• 
The samples (all de-identified) and labeled with study ID number will be processed, frozen, and shipped to a 
repository in the Coagulation Laboratory at Vitalant, Pittsburgh PA, under the direction of Mr. Michael Meyer. The 
inhibitor titer will be run by chromogenic Nijmegen Bethesda (CBA) assay real time, with confirmation on stored 


 
 
 
 
 
 
 
10
aliquots for those testing positive (> 0.6 B.U.). An aliquot of plasma sample will be assessed for trough FVIII 
chromogenic assay (aliquot of plasma sample).  The micriobiome (stool) sample will be shipped to the Vitalant Lab 
and transported to the Vascular Medicine Institute (VMI) in Pittsburgh, under the direction of Dr. Alison Morris. 
The PBMC sample will be snap frozen in dimethyl sulfoxide (DMSO) and stored in liquid nitrogen until batch testing 
for antigen-specific (FVIII) T cell responses by ELISPOT assay in the research laboratory of Dr. Kathleen Pratt, 
Uniformed Services of the Health Sciences (USUHS), Bethesda, MD. Samples for future testing (for hemophilia 
genotype or immunologic studies) will be stored indefinitely. 
• 
Stool sample: A small stool sample will be collected at home to assess genes and bacteria in the gut (microbiome) 
and placed in a small tube and returned in a container mailer to Vitalant, and couriered to VMI, Pittsburgh PA.  
• 
After the study physician determines eligibility, the subject will be randomly assigned to one of the two treatment 
strategies, Eloctate or Emicizumab. 
• 
The parent/caretaker will obtain Eloctate or Emicizumab by physician prescription through a clotting factor 
pharmacy of their choice. Eloctate will be administered by venipuncture, using a winged infusion needle (butterfly 
needle), heplock, or of required, by central line per physician discretion, over 5-10 minutes. Emicizumab will be 
administered by subcutaneous injection, using a small tuberculin needle over 1-2 minutes. It is anticipated that all 
study drug doses may be administered in the Hemophilia Center, or, for those living a distance away from the 
HTC, at a nearby infusion center, emergency room, by parent/ caretaker if trained, or by a visiting nurse. 
• 
All doses of study drug(s), including day, date, time, and dose will be recorded in subject diaries. All bleeds, 
including day, date, site, and resolution will be recorded by the parent/caretaker. All diaries will be returned to 
the HTC nurse coordinator at the monthly visits. 
• 
Subjects will begin Eloctate or Emicizumab, with the first dose as early as the day of consent and randomization, 
should the subject already have received a prescription and supply of study drug as part of standard care; 
otherwise, study drug(s) may be started as soon as the prescription is received. 
• 
The weekly dose of study drug, 65 IU/kg Eloctate; and 1.5 mg/kg Emicizumab (following the 3 mg/kg weekly x 4 
week-induction), will be begun following enrollment and screening, before the first bleed. The HTC nurse will 
discuss study visit scheduling with the parent/caretaker. The Screening/Baseline/Randomization and Treatment 
Initiation visit will last approximately 1 hour. 
 
FOLLOW-UP VISITS: 
Study Visit 2: Week 4 (Month 1) Follow-up Visit  
• 
Subject diaries will be reviewed for accuracy and completeness. Data will be extracted for frequency, type, and 
site of bleeds, including site, and for factor usage by day, date, time, and dose. 
• 
Study drug(s) use will be reviewed and more Eloctate or Emicizumab ordered as needed. 
• 
Concomitant medications will be recorded. 
• 
Assessment for adverse events will be completed. 
• 
Vital signs [blood pressure (BP), pulse (P), respiratory rate (RR), and oral temperature (ºC)] will be taken, and 
weight (kg) will be obtained. 
• 
A 3.8 ml (¾ tsp) blood sample will be collected for anti-FVIII chromogenic Nijmegen Bethesda assay (CBA) (plasma), 
antigen-specific (FVIII) T cell ELISPOT assay (PBMC), trough FVIII chromogenic activity (aliquot of plasma), and a 
sample (aliquot of plasma) stored for future studies (for hemophilia genetic or immunologic studies). All samples 
must be drawn prior to the Eloctate or Emicizumab dose. 
    


 
 
 
 
 
 
 
11
Study Visits 3, 5, 6, 8, 9, 11, 12:  Monthly Follow-up Visits (Can be done remotely or in person) 
• 
Subject diaries will be reviewed for accuracy and completeness. Data will be extracted for frequency and type of 
bleeds including site, and for factor usage by day, date, time, and dose. 
• 
Study drug(s) use will be reviewed and more Eloctate or Emicizumab ordered as needed. 
• 
Concomitant medications will be recorded. 
• 
Assessment for adverse events will be completed. 
 
Study Visits 4, 7, 10:  Quarterly Follow-up Visits 
• 
Subject diaries will be reviewed for accuracy and completeness. Data will be extracted for frequency, type, and 
site of bleeds, including site, and for factor usage by day, date, time, and dose. 
• 
Study drug(s) use will be reviewed and more Eloctate or Emicizumab ordered as needed. 
• 
Concomitant medications will be recorded. 
• 
Assessment for adverse events will be completed. 
• 
Vital signs [blood pressure (BP), pulse (P), respiratory rate (RR), and oral temperature (ºC)] will be taken, and 
weight (kg) will be obtained. 
• 
A 3.8 ml (¾ tsp) blood sample will be collected for anti-FVIII chromogenic Nijmegen Bethesda assay (CBA) (plasma), 
antigen-specific (FVIII) T cell ELISPOT assay (PBMC), trough FVIII chromogenic activity (aliquot of plasma), and a 
sample (aliquot of plasma) stored for future studies (for hemophilia genetic or immunologic studies). All samples 
must be drawn prior to the Eloctate or Emicizumab dose. Preferably, the ELISPOT assay will be drawn after 5 
exposure days, rather than week 12 or week 24, whichever is closer in time. 
 
END-OF-STUDY VISIT 
Study Visit 13:  Week 48, End-of-Study Visit 
• 
Subject diaries will be reviewed for accuracy and completeness. Data will be extracted for frequency, type, and 
site of bleeds, including site, and for study drug(s) usage by day, date, time, and dose. 
• 
Study drug(s) use will be reviewed. 
• 
Concomitant medications will be recorded. 
• 
Assessment for adverse events will be completed. 
• 
Vital signs [blood pressure (BP), pulse (P), respiratory rate (RR), and oral temperature (ºC)] will be taken, and 
weight (kg) will be obtained. 
• 
A 3.8 ml (¾ tsp) blood sample will be collected for anti-FVIII chromogenic Nijmegen Bethesda inhibitor assay (CBA) 
(plasma), antigen-specific (FVIII) T cell ELISPOT assay (PBMC), trough FVIII chromogenic activity (aliquot of plasma), 
and a sample (aliquot of plasma) stored for future studies (for hemophilia genetic or immunologic studies). All 
samples must be drawn prior to the Eloctate or Emicizumab doses. 
The total blood volume for all tests is 22.8 ml (4½ tsp) during the 48-week study. Monthly blood sampling will be 3.8 
ml (¾ tsp). Amounts of blood drawn will be less for children weighing less than 14 pounds. The Appendix detailing 
timing of visits and blood draws is attached on the last page of this protocol.  
 
 
 
3.3    
Data and Specimen Collection  


 
 
 
 
 
 
 
12
         
Data Collection. Data will be collected by the study physician and the HTC research nursing staff. All data required 
by the study protocol will be adequately documented in the source documents (e.g. hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ dairies, evaluation checklists, pharmacy dispensing records, lab assay 
results, copies or transcriptions certified after verification as being accurate copies, microfilm, magnetic media, subject 
files, pharmacy and laboratory records). Subject information will be captured and managed by electronic Case Report 
Forms via web-based electronic data capture by the INHIBIT DCC Data Management System. All information will be stored 
on their server in a secure database (housed in a locked room). No personal identifiers will be associated with the data. 
Subjects will be male children, > age 4 months up to 4 years, with severe hemophilia A, who fulfill the inclusion and 
exclusion criteria, and are cared for at one of the up to 41+ participating HTCs. Prognostic factors will be collected at 
baseline, include age, race, family history of inhibitors, and past circumcision. Follow-up data will be collected through 
week 48, including adherence (diary), bleeds (no., type, location treatment), factor use (dose, date), and if used, central 
line use or infection (time to, number).  Data collected from subjects at baseline and follow-up visits will include 
demographic, medical, and health information, including site and frequency of bleeds, procedures, hospitalizations, study  
drug(s) usage, and other medications. Source data will be stored at the HTC in a locked file cabinet in a locked room.  
Laboratory Specimens. A 3.8 ml (¾ tsp) blood sample, including a citrate (plasma) tube and a heparin (PBMC) tube 
will be drawn on all subjects at baseline, week 4, 12, 24, 36, and 48 of the trial. All samples will be drawn before 
administration of the study drug(s). All assays in the study are validated for small pediatric volumes, so total blood draw 
is 22.8 ml (4½ tsp) over the 48-week study for the anti-FVIII by chromogenic Nijmegen-modified Bethesda (CBA) assay, 
FVIII-specific T cell ELISPOT assay, trough FVIII (chromogenic assay), HLA, hemophilia genotype, and sample for storage 
(See Appendix). De-identified plasma (citrate) blood samples will be processed, frozen, and shipped to a repository under 
the direction of Mr. Michael Meyer, Coagulation Laboratory, Vitalant, Pittsburgh PA. The inhibitor (anti-FVIII) by 
chromogenic Nijmegen Bethesda assay (CBA) will be run real time on citrate plasma samples, with confirmation on stored 
aliquots for those testing positive (anti-FVIII > 0.6 B.U.). The hemophilia genotype and HLA type will be performed on buffy 
coat from the citrate sample at baseline only, and the FVIII trough by chromogenic assay will be run on an aliquot of the 
citrate sample. Samples for future testing will be stored up to 5 years after the end of the study. De-identified heparinized 
samples (PBMC) will be sent to the laboratory of Dr. Kathleen Pratt, Uniformed Services University of the Health Sciences 
(USUHS), Bethesda, MD. The PBMC sample will be snap frozen in dimethyl sulfoxide (DMSO) and stored in liquid nitrogen 
until batch testing for FVIII-specific T cell responses by ELISPOT assay. Samples for future testing (hemophilia genetic and 
immunology studies) will be stored indefinitely after the end of the study. Any part of subject blood samples that remains 
after the planned blood tests are done will either be destroyed or all identifiers and means of linking it back to the subject 
will be permanently removed prior to sending to repository for storage. The remaining sample will be used only for genetic 
and immunologic studies related to inhibitor development and hemophilia. The stool sample will be collected by patients 
at home, placed in a tube, and returned in a container to Vitalant, and transported locally to VMI, Pittsburgh PA. 
 
3.4 
Intervention  
The intervention for subjects randomized to the Prevent Trial is Eloctate 65 IU/kg IV weekly or Emicizumab 1.5 
mg/kg sq (after 4-week induction at 3 mg/kg/week) beginning before the first bleed. Eloctate is an FDA-approved drug 
that was shown in clinical trials to be safe and effective in prevention and treatment of bleeds, with improved half-life, 
and safety comparable to standard rFVIII with no differences in inhibitor frequency, thrombosis or allergic reaction. 
Emicizumab is an FDA-approved bispecific monoclonal antibody FVIII mimic that was shown in clinical trials to be safe and 
effective in the prevention of bleeds and is increasingly being used because of its simpler subcutaneous once weekly 
dosing. Parents, caretakers or patients will review and provide written consent, after which subjects will be randomized 
by computer-generated randomization codes by the INHIBIT DCC Data Management System. Data will be stored in a 
secure database, housed in a locked room, which will track each drug prescription and infusion, including the initial dose, 
to begin within 24 hours of enrollment, and continued weekly for 48 weeks. Eloctate will be reconstituted by two-way 
needle to allow transfer of the diluent into the lyophilized powder and given by slow intravenous infusion over 5-10 
minutes by heplock in an arm or hand vein; and Emicizumab will be given by subcutaneous injection by tuberculin syringe, 
which will allow transfer of the drug from the vial for injection over 1-2 minutes, in the abdomen, by HTC study nurse, 
visiting nurse, or trained parent/caretaker. Elocate and Emicizumab are covered by insurance, and prescriptions will be 
provided to patients/ parents/ caretakers by HTC MDs. Both drugs are FDA approved, Eloctate, exempt under IND 15996, 
and/or Emicizumab prophylaxis, as used in this trial, and thus, “exempt” from IND requirement.  
   


 
 
 
 
 
 
 
13
3.5  
Study Population  
The Prevent Trial will enroll 66 PUPs with severe hemophilia A, FVIII <0.01 IU/ml, > 4 months of age up to 4 years 
and no anti-FVIII antibody (anti-FVIII < 0.6 B.U.). The age chosen was based on our 2010 survey found that the median age 
at first bleed is 5.5 months, and 72% remain bleed-free at 4 months.  
Inclusion Criteria for the Prevent Trial include male children > 4 months and up to 4 years of age, severe hemophilia 
A (FVIII<0.01 U/ml), no evidence of an inhibitor (anti-FVIII < 0.6 B.U.), and no more than 3 exposures to FVIII, including 
FVIII for circumcision (factor VIII concentrate, cryoprecipitate or fresh frozen plasma).  Exclusion Criteria include acquired 
hemophilia or any bleeding disorder other than hemophilia A; use of an experimental drug(s); surgery anticipated in the 
next 48 weeks (except port placement); life expectancy less than 5 years; parent/caretaker unable or unwilling to keep a 
personal diary of bleeding frequency and study drug treatment, make monthly visits and blood draws; or other illness, 
condition, or reason in the opinion of the investigator that would make the patient unsuitable for the trial.   
Our 2019 survey indicates 420 infants with severe hemophilia A are expected to be born in the next 6 years at 31 
HTCs. With only 16% participating, we will enroll 66 severe hemophilia A PUPs over the 6-year enrollment (Table 1).  
    Table 1: 2019 Survey of 31 HTCs: Potential Subjects to Enroll on the Prevention Trial 
 
3.6  
Statistical Considerations 
      
The purpose of the Inhibitor Prevention Trial is to compare novel agents Eloctate and Emicizumab in the 
prevention of inhibitor formation. The results will be compared with hemophilia genotype, trough FVIII chromogenic 
activity, HLA, and FVIII-specific T cell response by ELISPOT assay from baseline, in order to determine correlation of each 
assay with inhibitor development over time by descriptive statistics. 
Demographic and other baseline characteristics will be summarized using descriptive statistics or counts and 
percentages, as appropriate. Data to be tabulated will include, but not be limited to, age, race, height, weight, frequency 
and site of bleeds (hematoma, joint, CNS), emicizumab use, circumcision bleeding and/or treatment, surgery or 
procedures. Data on treatment administration and adherence to assigned treatment will be presented. All subjects 
enrolled in the study and who receive Eloctate or Emicizumab will be included in the evaluation for safety. Adverse events 
will be classified using CTCAE System, Vol 4.03, 2010. Tabulations of adverse events by frequency, relatedness, and severity 
will be presented. Serious adverse events, laboratory parameters, and vital signs will be presented using descriptive 
statistics for changes over time. Concomitant medications and physical exam data will be summarized over time.  
 
The Primary Endpoint is the time to the development of an inhibitor, defined as antiFVIII >0.6 B.U. (CBA). We 
hypothesize that preemptive weekly prophylaxis with Emicizumab is non-inferior to Eloctate begun before the first bleed 
(excluding circumcision), in reducing or preventing inhibitor formation in children > 4 months up to 4 years of age with 
severe hemophilia A. The goal is to test the hypothesis that early treatment with Emicizumab is noninferior to Eloctate in 
reducing inhibitor formation. The primary analysis will be conducted according to the intention-to-treat principle. 
Sensitivity analyses will include a per protocol analysis of patients who initiated the assigned treatment regimen. 
 
 
Analysis of the Primary Endpoint: We propose to take advantage of prior historical information on inhibitor 
formation to improve power on the Prevention Trial. We propose a Bayesian design and analysis plan to test if Emicizumab 
is non-inferior to Eloctate by a 10% non-inferiority margin. Interim data presented by the PUPs A-Long trial (Königs, 
EAHAD, 2019) was used to inform a prior distribution for the Eloctate arm which incorporates the previously observed 
Eloctate data along with appropriate uncertainty to acknowledge these “borrowed” data were not observed concurrently 
in our study. This prior conceptually borrows the equivalent of 10 events (new inhibitors) occurring in our proposed study, 
allowing us to adjust our randomization ratios to assign more subjects to the lesser-studied Emicizumab arm, using 1:3 
Eloctate to Emicizumab randomization. A non-informative Bayesian prior will be used for the Emicizumab arm as there 
are no data published regarding inhibitor formation with this drug. The time to inhibitor formation will be compared 
between the two assigned treatment arms analyzed using piecewise exponential survival models to determine the 
probability of being inhibitor-free at 48 weeks. Monte-Carol Markov-Chains (MCMC) were utilized to determine the 
posterior probability of the outcome by operator characteristics. One interim analysis is planned to occur after 75% of the 
subjects are randomized. The trial will declare early success if Emicizumab demonstrates superiority to Eloctate at the 
Sev Hemophilia A Births (2016-18) 
No. Births In 6 yr         % of 6 yr Total to Enroll in 6 yr Trial 
Sample Size, Power for 6 yr Trial 
N = 210/ 3 yr 
N = 420 pt/ 6yr 
16% of 420 = ~ 66 in 6 yr 
66 PUPs: β=0.80, α=0.05 


 
 
 
 
 
 
 
14
interim. Otherwise, the trial will continue to the final analysis for non-inferiority. Extensive simulations were performed 
to set thresholds such that the type 1 error rate is maintained and power is maximized while recruiting 66 subjects. At the 
interim, once 75% of the subjects are randomized, the Bayesian posterior probability that Emicizumab is more likely to 
prevent inhibitor formation than Eloctate must be at least 99% to stop the trial. Assuming that the trial does not stop at 
the interim, in order to declare non-inferiority at the end of the study, the Bayesian posterior probability that Emicizumab 
is non-inferior to Eloctate in preventing inhibitor formation at the end of the study, must be 95.7%. If non-inferiority is 
met, then to declare superiority at the end of the trial, the Bayesian posterior probability that Emicizumab is more likely 
to prevent inhibitor formation than Eloctate must be at least 95.1%. This maintains the type 1 error rate at one-sided 5%, 
while having 85% power for non-inferiority and 28% power for superiority if we assume the true condition is that 
Emicizumab is 10% superior to Eloctate in prevention of inhibitor formation  (85% vs. 75% inhibitor-free rates). 
Subjects reaching the primary endpoint: The primary endpoint is inhibitor development, defined as anti-FVIII > 0.6 
B.U., by chromogenic Nijmegen Bethesda assay (CBA). A local lab anti-FVIII > 0.6 B.U. will be repeated on this, or if 
insufficient sample, or if insufficient, a repeat sample within 7 days, and a second sample obtained within 4 weeks for 
confirmation. A central lab anti-FVIII > 0.6 B.U. will be repeated within 4 weeks for confirmation. If confirmed, and a low-
responding inhibitor has developed, subjects will use Eloctate for breakthrough bleeds; if confirmed and a high-responding 
inhibitor has developed, rFVIIa will be used for breakthrough bleeds, per discretion of the subject’s treating physician: but, 
in either case, subjects will remain on study follow-up through week 48. For clarification, all detectable inhibitor levels will 
be repeated for confirmation. Prognostic factors collected at baseline, including age, race, family history of inhibitors, 
current or past emicizumab use, and past circumcision, will be compared by treatment arm. 
 
 
The Secondary Endpoints include a) safety measured by the number and frequency of bleeding events 
(hematoma, joint, CNS bleeds), the frequency ad time to central line infections; and the number and frequency of allergic 
reactions, and thrombosis; and b) mechanism of inhibitor prevention by FVIII-specific T cell ELISPOT (Ig, RNA), performed 
on an aliquot of PBMCs; and genotype, HLA, and trough chromogenic FVIII drawn on the buffy coat of anti-FVIII plasma 
samples. ELISPOT assays will be performed on T cell populations depleted of regulatory T cells (T reg) (CD4+CD25+FoxP3+) 
to determine the role of T regs in controlling immune response to FVIII.  
Analysis of Secondary Endpoints: The trial is not powered to analyze secondary endpoints statistically, but will 
collect these endpoints and perform descriptive statistics and correlations of safety and T cell mechanism by study arm, 
and with hemophilia genotype, HLA, and antigen-specific (FVIII) T cell responses (ELISPOT) from baseline, in order to 
determine correlation of each assay with inhibitor development over time by descriptive statistics. 
Subjects reaching secondary clinical endpoints: The clinical secondary endpoint will include safety measures, 
including the number and frequency of bleeding events (hematomas, joint, CNS bleeds) during the 48-week study, and 
the frequency and time to central line infections. Patient diaries will be reviewed monthly for bleeding frequency and site, 
and for dose and frequency of treatment.  If breakthrough bleeds occur, additional treatment will be given at the discretion 
of the subject’s physician, after which treatment may be continued at least weekly or escalated per physician discretion. 
Subjects will be closely monitored for adverse events, including allergic reactions, thrombosis, bleeding: these events will 
be summarized over time on study drug. Adverse events will be evaluated for frequency, relatedness, and severity.  
 
4.0  
Human Subjects 
4.1    
General Characteristics - Minority Inclusion and Non-Discriminatory Statements 
For the Inhibitor Prevention Trial, children > 4 months of age up to 4 years with severe hemophilia A, FVIII < 0.01 
U/ml, with no previous bleed requiring factor treatment (other than circumcision) and who are cared for at the Hemophilia 
Center, are eligible to participate. As hemophilia is an X-linked congenital disorder, >98% of whom are male, it is 
anticipated that the study population will be male, and as almost 90% are Caucasian, it is anticipated that the majority of 
subjects will be Caucasian males. For the trial, subjects will be limited to children > 4 months up to 4 years of age, with no 
previous bleeding requiring treatment, before the time of the first treatment.  We anticipate 90% of subjects will be 12 
months of age or younger and 10% over 12 months up to 4 years or more, and are limited to children, as inhibitor 
formation occurs in >95% within the first 50 exposure days to factor VIII treatment, typically within the first 2 years of life. 
Despite the benefits of standard prophylaxis three-times weekly to prevent joint bleeds and joint damage, the risk of 
inhibitor formation remains.  


 
 
 
 
 
 
 
15
            Currently there is no known effective approach in prevention of inhibitors, and this remains a major complication 
of hemophilia. The Prevention Trial will assess the effectiveness of preemptive weekly prophylaxis with Eloctate or 
Emicizumab begun before the first bleed (excluding circumcision). These agents will be given as part of clinical care to 
prevent bleeds. There will be no discrimination based on race or ethnicity (see Targeted/Planned Enrollment Table). The 
racial, gender and ethnic characteristics of the proposed subject population reflects the demographics of Pittsburgh, 
surrounding area, and the subject population of the University of Pittsburgh Medical Center. We shall attempt to recruit 
subjects in proportion to these demographics. All subjects will be screened prior to enrollment to confirm the diagnosis 
of severe hemophilia A, FVIII < 0.01 U/ml. Written, informed consent will be obtained from all subjects at the screening 
visit. Once eligibility is confirmed, visit 1 will be the start of enrollment. For the Prevent Trial, 66 subjects (1-4 locally), will 
be enrolled.   
 
4.2   
Inclusion of Children:  
   
The optimal approach to prevention and eradication of inhibitor formation in hemophilia is unknown.  Among those 
who develop inhibitors, 95% occur within 50 treatment exposures, usually in the first two years of life. Thus, inhibitor 
formation is primarily a problem in children, while inhibitor eradication is a problem of those who have already developed 
inhibitors, including children and adults. Thus, the trial is limited to male children with severe hemophilia A. 
 
4.3    
Inclusion/Exclusion Criteria  
 
Inclusion criteria: 
1. 
Male children > 4 months up to 4 years of age. 
2. 
Severe hemophilia A, FVIII < 0.01 U/ml. 
3. 
No evidence of an inhibitor, i.e. anti-FVIII < 0.6 BU. 
4. 
No more than 3 FVIII exposures (factor VIII concentrate, cryoprecipitate, or fresh frozen plasma), including 
circumcision. 
Exclusion criteria: 
Subjects will be excluded from study entry if any of the following exclusion criteria exist: 
1. 
Acquired hemophilia or any bleeding disorder other than hemophilia A. 
2. 
Unwilling to discontinue pre-trial Emicizumab before randomization. 
3. 
Use of an experimental drug(s). 
4. 
Surgery anticipated in the next 48 weeks (except port placement). 
5. 
Life expectancy less than 5 years. 
6. 
Parent/caretaker unable or unwilling to keep a personal diary of bleeding frequency and study drug treatment, 
make monthly visits and blood draws. 
7. 
Other illness, condition, or reason in the opinion of the investigator that would make the patient unsuitable for the 
trial. 
 
4.4 
Recruitment Procedures 
   
It is anticipated that 1-4 subjects will be enrolled in the Prevention Trial at this study site. Parents/caretakers of 
children with a diagnosis of severe hemophilia A, cared for at the HTC will be approached for participation in the trial. 
Parents/caretakers will specifically be contacted during routine clinic visits to determine if they or their child are interested 
in participating in the study. There will be no cold-calling. The study physicians, as their clinical care doctor sees FVIII-
deficient children at routine clinic visits, and will determine the parent/caretaker interest in their child’s study 
participation. If they are interested, their study physicians will discuss the study in further detail and review the informed 
consent. Each and every potential parent/ caretaker will discuss the study with their study physician and will be 
encouraged to take time to decide on participation and ask questions. If a parent/caretaker decides to take a consent 
form home for further viewing, they may contact a study nurse if they wish to participate, at which time; they will be 
scheduled again to visit/discuss/review the consent with their study physicians for enrollment. Discussion will include the 
purpose, safety issues, and risks and benefits of the study. Their study physicians will answer any questions and will obtain 
the consent.  No experimental procedures or interventions will occur until after informed consent is obtained. The   
investigator’s certification statement will be signed at the time consent is obtained. If any new information occurs during 
the conduct of the study, the parent/caretaker who has provided consent will be informed and will be re-consented with 


 
 
 
 
 
 
 
16
this information at the next visit. A de-identified prescreening/screening log will be kept, and all reasons for exclusion 
documented in study source documents and screening log. Parent/caretakers who read the consent form are free to 
refuse enrollment, and they will be free to withdraw their child’s consent at any time. If parents/ caretakers wish to 
withdraw consent, they may do so by addressing a letter to the principal investigator.   
 
Any data collected or blood samples drawn prior to the time of withdrawal will continue to be used, but no 
additional information or blood samples will be collected. Processed blood sample results will continue to be used for the 
research study; however, remaining samples will be destroyed or used as indicated by the parent/caretaker’s letter. The 
reason (e.g. AE, lost to follow-up, etc.) and date of withdrawal for all subjects withdrawn from this study will be recorded. 
Subject information will be captured and managed by study sites on electronic CRFs via the INHIBIT Trial DCC Data 
Management System. The sIRB may inspect the records of this study.  Every effort will be made to keep the subject’s 
personal medical data confidential.  Subject information will be captured and managed by study sites on electronic CRFs 
via the INHIBIT Trial DCC Data Management System. The sIRB may inspect the records of this study.  Every effort will be 
made to keep the subject’s personal medical data confidential.  
 
Demographic Chart: Targeted Enrollment for Study 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
2 
2 
Not Hispanic or Latino 
0 
64 
64 
Ethnic Category: Total of All Subjects * 
0 
66 
66 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
3 
3 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
0 
6 
6 
White 
0 
57 
57 
Racial Categories: Total of All Subjects * 
0 
66 
66 
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All Subjects.”                     
Subject eligibility for the study will be determined after screening. Subjects are to use their own supply of Eloctate 
or Emicizumab during the study. The parents/caretakers will sign informed consent and baseline labs will be drawn, 
including anti-FVIII level, FVIII-specific T cell assays (ELISPOT), FVIII trough level, hemophilia genotype and HLA type. 
Subject enrollment and screening will be conducted by the local Investigator, in communication with the INHIBIT Trial DCC 
Data Management System. Subjects will be considered enrolled in the study after all assessments have been completed 
during the Screening period and just prior to Eloctate or Emicizumab administration.  No subject may begin treatment 
prior to enrollment and assignment of a unique subject does not receive treatment. 
 
Subjects are only enrolled after the Investigator has verified that they are eligible. Subjects withdrawn from the 
study after enrollment and prior to receiving Eloctate or Emicizumab will be replaced. A subject eligibility form will be 
provided for the Investigator to verify that the Inclusion and Exclusion Criteria have been satisfied for each subject. The 
site (HTC) coordinator will upload the screening information to the INHIBIT Trial DCC Data Management System. Following 


 
 
 
 
 
 
 
17
confirmation of the subject’s eligibility along with the subject identification number, an accession number will be 
generated in the database. Once the subject identification number has been assigned, the subject may be randomized 
and then the assigned treatment initiated, Eloctate or Emicizumab, preferably in the morning.  
 
4.5    
Risk/Benefit Ratio 
   
Risk to Subjects  
There are risks associated with the study drug and having blood drawn. Eloctate and Emicizumab will be administered at the HTC, 
an outpatient infusion center, emergency room or at home by parent/caretakers/ or visiting nurses. Parents/caretakers will be 
asked to report any safety problems or side effects associated with Eloctate or Emicizumab administration. 
 
Risk of Discontinuing Emicizumab Prior to Randomization 
There are no known risks of discontinuing Emicizumab. If a bleed occurs, factor VIII will be given per physician discretion 
until it resolves and monitored by home treatment records, per standard of care. 
 
Risk of Blood Drawing  
There may be discomfort with drawing blood, which is common, occurring in up to 25%, or 25 in 100 individuals: this may 
include pain, lightheadedness, fainting, bruising, or bleeding or infection in the tissue around the vein.  This may be 
alleviated or reduced by applying pressure to the blood draw site for 5 minutes, and assuming a recumbent position (lying 
on the back). The risk of repeated blood draws is anemia, but this will be carefully monitored. Injections may rarely, in less 
than 1%, or less than 1 in 100 people, cause pain, soreness, redness, warmth, itching, numbness, tenderness, swelling, 
skin changes (discoloration, breakdown, or thickening), or swelling or lymph nodes near the injection site. 
 
Risk of Stool Collection 
There are no known risks of stool sample collection.  
 
Risk of Study Drug(s) Administration  
Treatment with Eloctate or Emicizumab may include minor pain or bruising at the infusion or injection site in up to 25%, 
or 25 in 100 individuals. A local anesthetic, Emla cream, may be used to minimize this discomfort. In young children, 
difficulty obtaining venous access due to small veins may require the placement of a central line. The insertion of a central 
line may reduce the discomfort of needle sticks and will be suggested at the discretion of the treating physician. Placement 
of central lines may cause bleeding, and thus additional factor treatment may be necessary. There is also the risk of 
anesthesia required for the line placement procedure. In addition, central lines may be complicated by infections that 
require hospitalization, antibiotics, and/or removal and replacement of the line. The insertion of a central line is part of 
clinical care and not required for this study.    
 
Risk of Inhibitor Development 
Inhibitor development occurs in 25-30%% or more of individuals with hemophilia A (Factor VIII deficiency). Of those who 
develop inhibitors, 95% do so within 50 exposure days, usually in childhood after 10-20 exposure days, by the age of 2. 
Currently there is no known way to prevent or eradicate inhibitor formation. Study subjects will be followed closely to 
monitor this risk, and samples for inhibitor assessment will be taken at several time points in the study to monitor for this 
possibility during the study. Should an inhibitor occur, subjects may use Eloctate or other FVIII product for immune 
tolerance, and rVIIa for bleeding at the discretion of the subject’s physician. Children with inhibitors will not be enrolled 
in this trial.  
 
Risk of Allergic or Anaphylactic Reaction                                                                                                      
Allergic-type reactions including anaphylaxis are rarely, if ever, reported for factor VIII products, including Eloctate or 
Emicizumab, and therefore, is expected to be rare, occurring in <0.001%, or less than 1 in 100,000 people. Symptoms may 
include chills, fever, nausea and vomiting, or rarely may include, in decreasing order of severity, death, anaphylaxis (life-
threatening difficulty breathing), low blood pressure, heart beat irregularity, increase in body fluids, paresthesia 
(numbness or prickling sensation), urticaria (hives), chest tightness, rash, pruritus (itching), edema (swelling), fever, and/or 


 
 
 
 
 
 
 
18
chills. Should these symptoms occur, benadryl, a medication which reduces inflammation, or an epi-pen, which causes 
vasoconstriction and bronchial smooth muscle relaxation, may be given, with close monitoring of these symptoms. 
Benadryl may cause drowsiness, dizziness or low blood pressure. An epi-pen may cause tachycardia, palpitations, 
sweating, nausea, and anxiety. Subjects will be monitored for these symptoms. Subjects will be monitored closely for early 
symptoms and signs of hypersensitivity reactions, including hives, generalized urticaria, angioedema, chest tightness, 
dyspnea, wheezing, faintness, hypotension, tachycardia, and anaphylaxis. If any subject develops signs or symptoms of an 
allergic type reaction or anaphylaxis during the administration of Eloctate or Emicizumab, the infusion will be stopped 
immediately, and appropriate medical care initiated.      
 
Risk of Thromboembolism/Thrombogenicity                                                                                                               
Historically hemostatic agents including Eloctate and Emicizumab rarely, if ever, are associated with the development of 
thromboembolic complications. In five adult patients with inhibitors taking FEIBA with Emicizumab in a clinical trial, 
thrombosis-related events occurred, so for that reason the use of FEIBA will not be allowed on this trial, and only factor 
rFVIIa will be allowed for bypass treatment of bleeds. There is the unlikely possibility, < 0.001%, or less than 1 per 100,000 
people, that Eloctate or Emicizumab, in the absence of FEIBA, could cause a clot, swelling, or inflammation in a vein. This 
risk will be very carefully monitored clinically. Should a clot occur, treatment would primarily consist of stopping the study 
treatment and/or removing the line in which it was given, if that is the source of the clot, as soon as possible. Should a 
bleeding episode occur during the study period, the subject will be treated with study Eloctate or, if an inhibitor occurs, 
rFVIIa, per physician discretion.  
 
Risk of Bleeding  
Because individuals with hemophilia are enrolling on a trial in which study drug(s) will be administered by infusion or 
injection, there is a risk of bleeding at the infusion or injection site. Subjects should contact their physicians if this occurs 
and/or seek medical attention. In the event that bleeding at the infusion site cannot be stopped with pressure, it may be 
necessary to use a stitch or an adhesive material to stop the bleeding. The devices used to administer the stitch or adhesive 
may cause the following negative side effects: bleeding, a build-up of blood known as a hematoma, infection, allergic 
reaction, nerve injury, and swelling. 
 
Other Risks 
Other risks reported in clinical trials of Eloctate and Emicizumab but not different than in the general hemophilia 
population include malaise (feeling unwell) and joint aching in 2% (2 per 100 people); and in 1% (1 per 100 people) feeling 
hot or cold, blood vessel disease, high blood pressure, slow heart rate, skin rash, and cough.  
 
Risk of Genetic Testing 
There is the possibility that if the results of the research studies involving a subject’s genetic material were to become 
generally known, this information could affect his ability to be insured, employed, or influence plans for future children, 
or have a negative impact on family relationships, and/or result in paternity suits or stigmatization. The biological sample 
or genetic material from subjects enrolled on this study may lead, in the future to new inventions or products. If new 
products were developed from the use of a subject’s biological sample or genetic material, no monetary or other reward 
that might result from the development of the new product would be provided to any subject. Since the genetic testing 
for this study is done by a research laboratory, results from this study laboratory cannot be released. 
 
Risk of Inadvertent Disclosure 
Study participation and related data will be protected to maintain confidentiality.  There is a possibility that the subject’s 
personal information could become generally known. This information could impact future insurability, employability, or 
reproduction plans, or have a negative impact on family relationships, and/or result in paternity suits or stigmatization. In 
order to reduce risks of disclosure or breach of confidentiality, the research related documents, blood samples and clinical 
information stored in his/her research files will be assigned an alphanumeric (letters and numbers) identifier (that do not 
contain personal identifiers). For this study, a linkage key for linking this number and the subject’s name will be kept at 
the HTC under lock and key by the HTC study physicians and the research staff.  Any publication arising from this study 
will not contain names or other identification unless study subjects grant permission in another signed consent. 


 
 
 
 
 
 
 
19
Potential Benefits 
The potential benefits include we will learn more about effective ways to prevent inhibitor formation in children. The 
subjects will be under close supervision during the study period. It is possible that administration of the Eloctate or 
Emicizumab weekly beginning before a bleed may decrease inhibitor formation in young children: however, this is 
currently not known, and is the purpose of this study. As both drugs prevent bleeds in patients with hemophilia, a potential 
benefit may be fewer bleeds: however, as bleeds may occur despite the use of these drug(s), treatment for break-through 
bleeding will be allowed at the discretion of the subject’s physician.  
 
Data Safety Monitoring Plan (DSMP) 
The local Data Safety Monitoring Plan for this trial will include the following requirements: 
   1. 
This study will identify, monitor, and report adverse events (AE) and unanticipated problems (UP).  
   2.  
Expedited reporting to the sIRB is required for unanticipated problems (UP) or unexpected serious adverse events 
(SAE) that may be related to the study protocol as follows: Any event or problem that is unexpected AND possibly, 
probably, or definitely related to study participation AND one of the following: 
• 
Is fatal, life-threatening, or serious (SAE + UP)………………REPORT within 7 calendar days 
• 
Suggests greater risk of harm to study participant(s) than was previously known or recognized…… REPORT within 
30 calendar days 
   3. 
Expedited SAE/UP reporting to the sIRB should include study and grant number, PI, description of the event or 
problem, why it merits expedited reporting, dates the event was reported to sIRB, FDA and other governing bodies, and 
any corrective action planned or taken in response to the event or problem, e.g. study suspension, consent or protocol 
changes, additional training or security measures. 
   4. 
Reporting is required by the investigator to and following the guidance of any other applicable oversight bodies, 
but not limited to sIRB, DSMB and FDA. All communication from these oversight bodies regarding any applicable SAE/UP 
must be reported to IRB according to the Data and Safety Monitoring Policy. 
 
The PI, Dr. Ragni, the Co-Investigators, Drs. Seaman and Xavier, Brooks, and Bertolet will be responsible for ongoing 
monitoring of all recruitment, data collection, and subject confidentiality procedures in the trial. They will meet at least 
bi-weekly to review all aspects of the study. Trial data, including all subjects enrolled, will be closely monitored by the PI 
and clinical research team to ensure subject safety and to ensure that procedures are in place to maintain privacy and 
confidentiality, progress of study, integrity of the data, procedure reviews and for discussion of pertinent scientific 
literature or events which could affect the benefit to risk ratio. All serious and unexpected adverse events and/or major 
breaches of confidentiality will be reported to the sIRB according to regulations outlined in the IRB Reference Manual for 
the Use of Human Subjects.  All AE’s, SAE’s generated from the HTC will be sent following reporting guidelines to sIRB. A 
report summarizing the above local and central DSMP activities will be submitted to the sIRB at the time of annual renewal. 
 
Data will be reviewed on an ongoing basis by the Data Safety Monitoring Board (DSMB). DSMB members will have 
expertise in hematology, hemophilia, and statistics, and all will have voting rights.  The DSMB will review data for all 
subjects enrolled in the study protocol and determine if the risk benefit ratio is sufficiently favorable that it is appropriate 
to continue the trial. 
 
The events are: 
• 
A previously untreated subject (PUP) develops a positive Bethesda assay result (anti-FVIII > 0.6 B.U.) whether at 
the local laboratory or the central laboratory. 
• 
A subject develops anaphylaxis in association with administration of Eloctate or Emicizumab. 
• 
A subject develops a thrombotic event in association with the administration prophylaxis with the exception of 
intravenous (IV) infusion site thrombophlebitis. 
• 
A subject develops severe or catastrophic bleeding requiring prolonged and/or intense treatment exceeding 
study-related dosing.  
• 
A subject develops a Grade 2 or greater allergic reaction in association with Eloctate or Emicizumab, defined as 
follows using the CTCAE grading. 
o Grade 2    Transient flushing, rash, or drug fever > 38º C. 


 
 
 
 
 
 
 
20
o Grade 3    Symptomatic bronchospasm; with or without urticaria; parenteral medication(s) indicated;               
 
    allergy-related edema/angioedema; hypotension 
o Grade 4    Anaphylaxis 
 
In addition to halting enrollment and further treatment, such an event will be handled as a serious adverse event (SAE) 
and reported in an expedited time frame to the FDA. The data concerning the event and subject with input from the site 
HTC Co-Investigator will be reviewed by the DSMB along with all other available data to determine appropriate follow-up, 
with a decision to continue enrollment and treatment of subjects at that time. If the decision is made to discontinue the 
study, the Co-Investigators will be notified and the appropriate final study evaluations (Last Visit) will be performed on all 
subjects enrolled in the study at that time.   
 
Additionally, the following may also stop further subject enrollment and treatment.   
• 
The DSMB warrants temporary suspension of enrollment for further review of data generated to date. 
• 
The PI determines that a medically important event warrants further evaluation by the DSMB. 
In these cases the required follow-up as determined by the PI and/or DSMB will be performed.  The DSMB will determine 
if it is appropriate to reinitiate enrollment in the study.  The sIRB will be informed of such decisions. 
 
Local Adverse Event Reporting 
All adverse events experienced by study subjects from the consent until 30 days after administration is to be recorded on 
the CRF, regardless of the severity of the event or its relationship to study treatment.  
 
The serious AE reporting procedures are based on the “Cancer Therapy Evaluation Program: Common Terminology Criteria 
for Adverse Events” (CTCAE) v 4.03, June 14, 2010. Subjects will report to HTC co-investigator or to the HTC nursing 
coordinator, any AE or SAE. AE’s will be classified as mild (does not interfere with routine activities), moderate (interferes 
somewhat with routine activities), or severe (impossible to perform routine activities). The following algorithm will be 
used to assess the causality of all AE’s:  
 
• Not related: The event can readily be explained by factors not involving Eloctate or Emicizumab, and a temporal 
relationship with Eloctate or Emicizumab, does not exist. 
• Possibly related: A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of Eloctate or Emicizumab, but which could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
• Probably related: The temporal relationship between the administration Eloctate or Emicizumab is compelling, and 
the event cannot be explained by the subject’s medical condition or other therapies. 
• Related: The event follows a reasonable temporal sequence from administration of Eloctate or Emicizumab, follows a 
known or suspected response pattern to Eloctate or Emicizumab, is confirmed by improvement upon stopping the 
agent (dechallenge) and reappears upon repeated exposure to Eloctate or Emicizumab. 
All AEs, regardless of severity, will be followed up by HTC Investigator until satisfactory resolution. All subjects 
experiencing AEs will be monitored until symptoms subside and any abnormal laboratory values have returned to baseline, 
or until there is a satisfactory explanation for the changes observed, or until death, in which case a full pathologist's report 
will be supplied, if possible. Withdrawal from the clinical study and therapeutic measures shall be at the discretion of the 
investigator.  
 
As required by the University of Pittsburgh Institutional Review Board, if there is an unexpected, serious internal adverse 
event (life threatening or fatal) that is determined to be associated with Eloctate or Emicizumab, it will be reported to the 
sIRB within 24 hours. If the event is not serious, unexpected or related to either agent, it will be reported within 5 days. 
External adverse events that are unexpected, related to either agent and determined to place the subject at greater risk 
than previously recognized will be reported within 10 working days of notification. 
 
 
 
 


 
 
 
 
 
 
 
21
Adverse Event (AE) Reporting at sites 
All events must be assessed to determine the following: 
• 
If the event meets the criteria for an SAE   
• 
The relationship of the event to study treatment   
• 
The severity of the event  
An AE is any untoward medical occurrence in a subject in whom a pharmaceutical product is administered and that does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
pharmaceutical product, whether or not related to the pharmaceutical product. 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
results in death 
• 
in the view of the Investigator, places the subject at immediate risk of death (a life-threatening event), but does 
not include an event that, had it occurred in a more severe form, might have caused death 
• 
requires inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity, or 
• 
results in a congenital anomaly/birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition above. (Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room or convulsions 
occurring at home that do not require an inpatient hospitalization.) 
 
In this study, the following events are considered medically important and must be reported as SAEs: 
• 
A subject develops a positive (chromogenic Nijmegen Bethesda) inhibitor assay result (> 0.6 B.U.) whether at the 
local laboratory or the central laboratory. 
• 
A subject develops anaphylaxis in association with administration of Eloctate or Emicizumab. 
• 
A subject develops a thrombotic event in association with the administration of Eloctate or Emicizumab, with the 
exception of intravenous (IV) infusion site thrombophlebitis. 
• 
A subject develops a Grade 2 or greater allergic reaction in association with administration of Eloctate or 
Emicizumab defined as follows using the CTCAE Evaluation. 
o Grade 2    Transient flushing, rash, or drug fever > 38º C. 
o Grade 3    Symptomatic bronchospasm; with or without urticaria; parenteral medication(s) indicated;             
 
    allergy-related edema/angioedema; hypotension 
o Grade 4    Anaphylaxis 
 
Any SAE experienced by the subject from the time of dosing until the end of study, 30 days after Eloctate or Emicizumab 
administration is to be recorded on an SAE Form, regardless of the severity of the event or its relationship to study 
treatment.  SAEs must be reported to the PI. Any SAE ongoing when the subject completes the study or discontinues from 
the study will be followed by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
 
A serious pre-treatment event associated with the conduct of the study experienced by the subject after signing the ICF, 
but before administration of study treatment is to be recorded on the Serious Adverse Reaction (SAE) CRF and faxed (and 
electronically uploaded) to the PI within 24 hours of the study site staff becoming aware of the event.  
 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site will formally notify the PI 
within 24 hours of the study site staff becoming aware of the SAE. It is the Investigator’s responsibility to ensure that the 
SAE reporting information and procedures are followed. A death must be recorded on the appropriate CRF and electronic 
CRF (eCRF).  All causes of death will be reported as SAEs.   
 
 
 
 


 
 
 
 
 
 
 
22
 
 
 
 
                  
 
Reporting Information for SAEs 
Any SAE that occurs after any subject receives Eloctate or Emicizumab (Day 1) and any serious pre-
treatment events must be reported to the PI within 24 hours of the study site staff becoming aware 
of the event.  This report must be submitted regardless of whether or not the subject has undergone 
any study-related procedures or received study treatment and regardless of severity or relationship 
to study treatment. To report initial or follow-up SAE information and serious pre-treatment medical 
event information, enter the information in the CRF and web-based CRF.  If the database is not 
available, fax a completed SAE form to the following or, if fax is not possible, call the number below 
to report the information. Emergency Contact Numbers:  
Fax: 412-209-7281  
Phone: 412-209-7288 (daytime) 
Phone: 1-888-990-1100 (evening and weekends) 
 
 
Safety Classifications and Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and SAEs to the study treatment: 
 
 
Relationship of Event to Study Treatment 
__________________________________________________________________________________________________ 
Unrelated 
Any event that does not follow a reasonable temporal sequence from administration 
of study treatment AND that is likely to have been produced independently by the 
subject’s clinical state or other modes of therapy administered to the subject. 
Unlikely 
Any event that does not follow a reasonable temporal sequence from administration 
of study treatment OR that is likely to have been produced by the subject’s clinical 
state or other modes of therapy administered to the subject. 
Possibly 
Any reaction that follows a reasonable temporal sequence from administration of 
study treatment OR that follows a known response pattern to the suspected drug AND 
that could not be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
Related 
Any reaction that follows a reasonable temporal sequence from administration of 
study treatment AND that follows a known response pattern to the suspected drug 
AND that recurs with re-challenge, AND/OR is improved by stopping the drug or 
reducing the dose. 
__________________________________________________________________________________________________ 
 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
 
Severity of Event 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; 
does not influence performance or functioning; prescription drug not ordinarily 
needed for relief of symptom(s) but may be given because of personality of subject. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of 
daily activity is influenced; subject is able to continue in study; treatment for 
symptom(s) may be needed. 


 
 
 
 
 
 
 
23
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
 
A prescheduled or elective procedure or a routinely scheduled treatment will not be allowed during the study period.   
 
5.0  
Costs and Payments 
5.1   Research Study Costs  
No costs will be incurred by the subjects or their parents/care providers for their participation in this study for 
research procedures. sIRB preparation costs will be covered, along with research procedures, including screening visits, 
blood draws for local and central laboratory assays, blood processing, shipping, and HTC charges and services related this 
study protocol. Eloctate or Emicizumab in this study will be the patient’s own study drug. The budget is not designed to 
cover the cost of study drugs. Should a central line be suggested by the subject’s physician, there will be no payment or 
compensation as this is considered standard clinical care. Research blood draw kits will be provided by the University of 
Pittsburgh coordinating center for use at local HTC’s. Any other expenses for this study not listed above, will be paid by 
the local HTC. 
5.2   Research Study Payments 
 
Parents/caretakers will receive compensation for their child’s participation in this study, to help defray the cost 
of meals, travel, and time lost from work.  There will be no additional costs to parents/caretakers for their child’s 
participation in this study beyond the charges for routine medical care. The study is funded by HRSA. Compensation is 
based on study visits completed. Subjects will receive $40 per visit for up to 13 visits during the 48-week trial. If a subject 
completes all visits, the total amount will be $480.00. If a subject does not complete any part of the scheduled study days, 
compensation for missed visits will not be made. If, for whatever reason a subject completes part, but not all of the study, 
the terms of payment will be determined by the number of visits completed.   
 
6.0  
Appendices 
6.1   Qualifications of Investigators 
    Dr. Margaret Ragni is a Professor of Medicine, University of Pittsburgh, and Director of the Hemophilia Center of Western PA, 
and has conducted numerous clinical research studies at the University, investigator-initiated and in collaboration with the CDC, 
FDA, and pharmaceuticals. She is an expert in hemophilia and in the management of its complications, including AIDS and 
hepatitis, and hemophilia inhibitor formation. 
     Dr. Craig Seaman is an Assistant Professor of Medicine and Associate Director of the Hemophilia Center of Western PA. He has 
focused his work on von Willebrand disease, bleeding scores, VWF and cardiovascular disease and aging. He has published case 
studies of patients with VWD 
     Dr. Frederico Xavier is an Assistant Professor of Pediatrics and Associate Director of the Hemophilia Center of Western PA. He 
has worked with Dr. Ragni at the Hemophilia Center of Western PA to provide care for children with hemophilia and under her 
mentorship on numerous research studies in congenital hemostasis and thrombosis. Dr. Xavier has in depth experience as a 
pediatrician managing children and young adults with hemophilia, von Willebrand disease, and other congenital hemostasis and 
thrombosis disorders. He serves with as local investigator on this trial. 
    Debbie Vehec, Clinical Nurse, MSN, RN, will head the nursing and coordinating aspects of this trial. She has long 
experience in the initiation, monitoring, and coordination of clinical trials, including reporting adverse events, timely 
communication. 
    Dana Ivanco, Regulatory Coordinator, is a clinical research regulatory coordinator who has had long experience in 
submission, revision, modification, and all aspects of regulatory protocol work, clinical trials operation, and has served as 
reviewer for the University of Pittsburgh IRB.  
    Dr. Maria Mori Brooks, lead DCC, is Professor of Epidemiology and Biostatistics and has over 25 years’ experience with 
clinical trials, study design, coordination and statistical analysis for NIH-sponsored multicenter clinical trials. She is one of 
the Co-Directors of the Epidemiology Data Center, University of Pittsburgh. 
    Dr. Marnie Bertolet, lead statistician, is an Assistant Professor of Epidemiology and Biostatistics and has over 10 years’ 
experience in the design and conduct of multicenter trials at the Epidemiology Data Center, University of Pittsburgh. She 
has expertise in Bayesian statistical methods and design. 


 
 
 
 
 
 
 
24
    Tamara Haller, Data Manager, is an experienced data manager at the Epidemiology Data Center, University of 
Pittsburgh, who has overseen data collection and data management for numerous federally-funded clinical trials and 
cohort studies. 
     Dr. Alison Morris is a Professor of Medicine University of Pittsburgh, Pulmonary, Allergy and Critical Care Disease, who heads 
the Microbiome Studies at Pitt and will coordinate stool microbiome samples. 
 
6.2    
Bibliography/References  
1. 
Hay CR. The epidemiology of factor VIII inhibitors. Haemophilia 2006; 12: Suppl 6: 23-28. 
2. 
Fischer K, Iorio A, Hollingsworth R, Makris M. FVIII inhibitor development according to concentrate: data from the 
EUHASS registry excluding overlap with other studies. Haemophilia 2016; 22: 36 (letter). 
3. 
Iorio A, Halimeh S, Holzauer S, Goldenberg N, Marchesini E, Marcucci M, Young G, Bidlingmaier C, Brandao LR, 
Ettingshausen CE, Gingeri A, Kenet G, Knöfler R, Kreuz W, Kurnik K, Manner D, Santagostino E, Mannucci PM, 
Nowak-Göttl U. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-
derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8: 1256-1265. 
4. 
Ragni MV, Ojeifo O, Hill K, Feng J, Yan J, Hill KA, Sommer SS, Trucco M, Brambilla DJ, and the Hemophilia Inhibitor 
Study Group. Risk factors for inhibitor formation in hemophilia: A Prevalent Case-Control Study. Haemophilia 
2009; 15: 1074-1082. 
5. 
Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Recombinant factor VIII for the treatment of previously untreated 
patients with hemophilia A: Safety, efficacy, and development of inhibitors. N Engl J Med 1993; 328: 453-459. 
6.  
Schwartz RS, Abildgaard CF, Aledort LM, Arkin S, Blood AL, Brackmann HH, Brettler DB, Fukui H,  Hilgartner MW, 
Inwood MJ, Kasper CK, Kernoff PBA, Levine PH, Lusher JM, Mannucci PM, Scharrer I, MacKenzie MA, Pancham N, 
Kuo HS, Allred RU. Human recombinant DNA-derived antihemophilic 
factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990; 323: 1800-1805. 
7. 
Rothschild C, Laurian Y, Satre EP, Borel-Derlon A, Chambost H, Moreau P, Goudemand J, Parquet A, Peynet J, 
Vicariot M, Beurrier P, Claeyssens S, Durin A, Faradji A, Fressinaud E, Gaillard S, Guerin V, Guerois C, Pernod G, 
Pouzol P, Schved JF, Gazengel C. French previously untreated patients with severe hemophilia A after exposure to 
recombinant factor VIII: Incidence of inhibitor and evaluation of  immune tolerance. Thromb Haemost 1998; 80: 
779-783. 
8. 
Lusher JM, Lee CA, Kessler CM, Bedrosian CL. The safety and efficacy of B-domain deleted recombinant factor VIII 
concentrate in patients with severe hemophilia A. Haemophilia 2003; 9: 38-49. 
9. 
Musso R, Santagostino E, Faradji A, Iorio A, van der Meer J, Ingerslev J, Lambert T, Maas-Enriquez M, Gorina E. 
Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: Experience in the standard clinical 
setting. Thromb Haemost 2008; 99: 52-58. 
10. 
Kurnik K, Bidlingmaier C, Engl W, Chehadeh H, Reipert B, Auerswald G. New early prophylaxis regimen that avoids 
immunological danger signals can reduce FVIII inhibitor development. Haemophilia 2010; 16: 256-262. 
11.   
Auerswald G, Kurnik K, Aledort LM, Chehadeh H, Loew-Baselli A, Steinitz K, Reininger AJ. The EPIC Study: a lesson 
to learn. Haemophilia 2015; 21: 622-628.  
12. 
Strauss T, Ravid B Martinowitz U, Bashari D, Kenet G. Early exposure to recombinant factor concentrates may 
increase inhibitor development: A single center cohort study.  Haemophilia 2011;17: 625-629. 
13. 
Kulkowska A, Komvska V, Jansen M, Lagrva P. Low incidence of factor VIII inhibitors in previously untreated 
patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate ®: interim report from 
an ongoing prospective clinical study. Haemophilia 2011; 17: 399-406. 
14. 
Gouw SC, van den Berg HM, Fischer K, Auerswald G, Carcao M, Chalmers E, Chambost H, Kurnik K, Liesner R, Petrini 
P, Platokouki H, Altisent C, Oldenburg J, Nolan B, Garrido RP, Mancuso ME, Rafowicz A, Williams M, Clausen N, 
Middelburg RA, Ljung R, van der Bom JG. Intensity of factor VIII treatment and inhibitor development in children 
with severe hemophilia A: the RODIN study. Blood 2013; 121: 4046-4055. 
15. 
Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, 
 
Varadarajan R, Karimi M, Manglani MV, Ross C, Young G, Seth T, Apte S, Nayak DM, Santagostino E, 
 
Mancuso ME, Gonzalez ACS, Mahlangu JN, Boix SB, Cergueira M, Ewing NP, Male C, Owaidah T, Arellano VS,   
 
Kobrinsky NL, Majumdar S, Garrido RP, Sachdeva A, Simpson M, Thomas M, Zanon E, Antmen B, Kavakli K, 
 
Manco-Johnson MJ, Martinez M, Marzouka E, Mazzucconi MG, Neme D, Bravo AP, Aguilera RP, Prezotti A, 


 
 
 
 
 
 
 
25
 
Schmitt K, Wicklund BM Zulfikar B, Rosendaal FR. A randomized trial of factor VIII and neutralizing antibodies in 
 
hemophilia A. N Engl J Med 2016; 374: 2054-2064. 
16.  
Ragni MV, Bontempo FA, Lewis JH. Disappearance of inhibitor to factor VIII in HIV-infected hemophiliacs with 
progression to AIDS or severe ARC.  Transfusion 1989; 29: 447-449.   
17. 
Bray GL, Kroner BL, Arkin S, Aledort L, Hilgartner MW, Eyster ME, Ragni MV, Goedert JJ.  Loss of high-responder 
inhibitors in patients with severe hemophilia A and HIV infection.  Am J Hematol 1993; 42: 375-379. 
18. 
Soucie JM, Symons J, Evatt B, Brettler D, Huszti H, Linden J. Home-based infusion therapy and hospitalization for 
bleeding complications among males with hemophilia. Haemophilia 2001; 7:198-206. 
19. 
Goudemand J. Pharmacoeconomic aspects of inhibitor treatment. Eur J Haematol 1998 (Suppl); 63: 24-27.  
20. 
Walsh CE, Soucie JM, Miller CH. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol 
2015; 90:400-405. 
 
21. 
DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, 
 
outcome predictors. Thromb Haemost 2002; 87: 52-57. 
22. 
EMEA. Report on expert meeting on FVIII products and inhibitors. February 28 - March 2, 2006. 
http://www.emea.europa.eu/pdfs/human/bpwg/12385/2006en.pdf, accessed April 26 2010. 
23. 
Gouw SC, van der Bom JG, Ljung R, Escruiola C, Cid AR, Claeyssens-Donadel S, van Geet C, Kenet G, Mäkipernaa A, 
Claudio-Molinari A,  Muntean W, Kobelt R, Rivard G, Santagostino E, Thomas A, van den Berg HM. Factor VIII 
products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231-239.  
24. 
Matzinger P. The danger model: a renewed sense of self. Science 2002; 296: 301-305. 
25. 
Powell JS, Josephson C, Quon D, Ragni MV, Cheng G, Li E, Jiang H, Dumont JA, Goyal J, Zhang X, Sommer J, McCue 
J, Barbetti M, Luk A, Pierce GF. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in 
hemophilia A patients. Blood 2012; 119: 3031-3037. 
26. 
Mahlangu J, Powell J, Ragni M, Chowdary P, Josephson N, Pabinger N, Hanabusa H, Gupta N, Kulkarni R,Fogarty P, 
Perry D, Shapiro A, Pasi J, Apte S, Krassova S, Jiang J, Li S, Cristiano LM,  Neelakantan S, Greblikas F, Goyal J, 
Sommer J, Dumont JA, Innes A, Nugent K, Brennan A, Vigiliani G, Luk A, Pierce GF. Phase 3 study of long-acting 
recombinant factor VIIIFc in hemophilia A. Blood 2014; 123: 317-325. 
27. 
Borel Y. Haptens bound to self IgG induce immunologic tolerance, while when coupled to syngeneic spleen cells 
they induce immune suppression. Immunol Rev 1980; 50: 71-104. 
28. 
Ephrem A, Chamat S, Miquel C Fisson S, Mouthon L, Calguiri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, 
Cohen JL, Salomon BL, Kazatchkine MD, Kaveri SV, Misra N. Expansion of CD4+CD25+ regulatory T cells by 
intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 
2008; 111: 715-722. 
29. 
DeGroot AS, Moise L, McMurry JA, Wambre E, van Overtvelt L, Moingeon P, Scott DW, Martin W.
 
Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes”. Blood 2008; 112:  3303-3311.  
30. 
Lei TC, Scott DW. Induction of tolerance to factor VIII inhibitor by gene therapy with immunodominant A2 and C2 
domains presented by B cells as Ig fusion proteins. Blood 2005; 105: 4865-4870. 
31. 
Liu T, Hoehn T, Hoehn S, Patarroyo-White S, Pierce G, Jiang H. Evaluation of antibody responses to rFVIIIFc 
compared to Xyntha and Advate in hemophilia A mice. Haemophilia 2012; 18 (Suppl S3):41. 
32. 
Ragni MV, Alabek M, Malec LM. Inhibitor development in two cousins receiving factor VIII and factor VIII-Fc fusion 
protein. Haemophilia 2016; 22; e462-e464, doi:10.1111/hae.13032. PMID: 27501368 
33. 
Malec LM, Journeycake J, Ragni MV. Extended half-life factor VIII and immune tolerance induction in hemophilia: 
A case series. Haemophilia 2016; 22: e562-e564, doi:1111/hae.13064.  PMID: 27640873 
34. 
Jiang H, Lillicrap D, Patarroyo-White S, Liu T, Qian X, Ciaran D, Powell S, Keller T, McMurray M, Labelle A, Nagy D, 
 
Vargas JA, Zhou S, Couto LB, Pierce GF. Multi-year therapeutic benefit of AAV serotypes 2, 6, 8 delivering 
 
factor VIII to hemophilia A mice and dogs. Blood 2006; 108: 107-115. 
35. 
Xu L, Nichols TC, Sarkar R, McCouquodale S, Bellinger DA, Ponder KP. Absence of a desmopressin response after 
therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc Natl 
Acad Sci 2005; 102: 6080-6085.    
36.  
Ragni MV, Wu W, Liang X, Cortese-Hassett A, Lu L. Factor VIII-pulsed tolerogenic dendritic cells reduce F.VIII 
inhibitor formation in the murine hemophilia A model. Exp Hematol 2009; 37: 744-754. 
37. 
Matsui H, Shibata M, Brown B, Labelle A, Hegadorn C, Andrews C, Chuah M, Van den Driessche T, Miao CH, Hough 
C, Lillicrap D. A murine model for induction of long-term immunologic tolerance to factor VIII does not require 


 
 
 
 
 
 
 
26
persistent detectable levels of plasma factor VIII and involves contributions from FoxP3+ T regulatory cells. Blood 
2009; 114: 677-685. 
38. 
Qadura M, Waters B, Burnett E, Chegeni R, Bradshaw S, Hough C, Othman M, Lillicrap D. Recombinant and plasma-
derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice. Blood 2009; 
114: 871-880. 
39. 
Lollar P. Pathogenic antibodies to coagulation factors. Part one: factor VIII and factor IX. J Thromb Haemost 2004; 
2: 1082-1095. 
40. 
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson L, Funk S, 
Jacobon L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, 
Mathew P, Matsunaga A, Medeiros d, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, 
Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J 
Med 2007; 357: 535-544. 
41. 
National Hemophilia Foundation. Medical and Scientific Advisory Council (MASAC) Recommendation concerning 
prophylaxis: regular administration of clotting factor concentrate to prevent bleeding (#179). 
 
http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=1007.  
42. 
Ragni MV, Kessler CM, Fogarty PJ, Josephson NC, Neff AT, Raffini LJ. Survey of current prophylaxis practice in U.S. 
hemophilia treatment centers. Haemophilia 2012; 18: 63-68.  
43. 
Gouw SC, van der Bom JG, van den Berg HM. Treatment-related risk factors of inhibitor development in previously 
untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109:  4648-4654. 
44. 
Ljung R, Chambost H, Stain AM, DiMichele D. Haemophilia in the first years of life. Haemophilia 2008; Suppl 3: 
 
188-195. 
45. 
Ragni MV, Kessler CM, Lozier JN. Clinical Aspects and Therapy of Hemophilia, in Hematology: Basic Principles and 
Practice, Hoffman R, Benz EJ, Shattil SJ, Furie R, Silberstein LE, McGlave P, Heslop H, eds, 5th Edition, Churchill 
Livingstone, 2009; 1911-1930. 
46. 
Cines DB, Blajchman MA, High KA, Bussel JB; for the State-of-the-Science Symposium Hemostasis-
 
Thrombosis Committee. Clinical trial opportunities in Hemostasis and Thrombosis: Proceedings of an NHLBI State-
 
of-the-Science Symposium. Am J Med 2012; 87: 235-238. 
47.  
Gouw SC van den Berg HM, Le Cessie S, van der Bom JG. Treatment characteristics and the risk of inhibitor 
development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J 
Thromb Haemost 2007; 5: 1383-1390. 
48.  
Feldman BM, Pai M, Rivard GE, Israels S, Poon MC, Demers C, Robinson S, Luke KJ, Wu JKM, Gill K, Lillicrap D, 
 
Babyn P, McLimont M, Blanchette S. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 
 
years of the Canadian Hemophilia Primary Prophylaxis Study. J Thromb  Haemost 2006; 4: 1228-1236. 
49. 
Rodriguez V, Titapiwatanakun R, Moir C, Schmidt KA, Pruthi RK. To circumcise or not to circumcise?  Circumcision 
in patients with bleeding disorders. Haemophilia 2010; 16: 272-276. 
50. 
Kavakli K, Aledort LM. Circumcision and hemophilia: a perspective. Haemophilia 1998; 4:1-3. 
51. 
Personal communication, Kenet G, Jerusalem Israel, April 19, 2010. 
52. 
Personal communication, Potgieter JC, University of Pretoria, South Africa, May 6, 2010. 
53. 
Personal communication, Mahlangu JN, Johannesburg, South Africa, May 6, 2010. 
54. 
Mahlangu JN. Haemophilia care in South Africa: 2004-2007 look back. Haemophilia 2009; 15: 135-141 
55. 
Kaczorowski DJ, Mollen KP, Edmonds R, Billiar TR. Early events in the recognition of danger signals after tissue 
injury. J Leukoc Biol 2008; 83: 546-552. 
56. 
Dumont JA, Low SC, Peters RT, Bitonti AJ. Monomeric Fc fusions: impact on pharmacokinetic and biological activity 
of protein therapeutics. BioDrugs 2006; 20: 151-160. 
57. 
Dumont JA, Liu T, Low SC, Zhang X, Kamphaus G, Sakarofas P, Fraley C, Drager D. Reidy T, McCue J, Franck HW, 
Merricks EP, Nichols TC, Bitonti AJ, Pierce FG. Jiang H. Prolonged activity of a recombinant factor FVIII-fusion 
protein in hemophilia A mice and dogs. Blood 2012; 119: 3024-3030. 
58. 
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7: 715-725. 
59. 
Peters RT, Toby G, Lu Q, Liu T, Kulman JD, Low SC, Bitonti AJ, Pierce GF. Biochemical and functional characterization 
 
of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost 2013; 11: 132-141. 


 
 
 
 
 
 
 
27
60. 
Collins PW, Blanchette VS, Fischer K, Bjorkman S, Oh M, Fritsch S, Schroth P, Spotts G, Astermakr J, Ewenstein B. 
Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for 
severe hemophilia A.  J Thromb  Haemost 2009; 7: 413-420.      
61. 
Rath T, Baker K, Dumont JA, Peters RT, Jian H, Qiao SW, Lencer WI, Pierce GF, Blumberg RS. Fc-fusion proteins and 
FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol 2015; 35: 235-254. 
62. 
Mukovozov I, Sablijc T, Hortelano G, Ofosu FA. Factors that contribute to the immunogenicity of therapeutic 
recombinant human proteins. Thromb Haemost 2008; 99: 874-882. 
63. 
Hu G, Guo D, Key NS, Conti-Fine BM. Cytokine production by CD4+ T cells specific for coagulation factor VIII in 
healthy subjects and haemophilia A patients. Thromb Haemost 2007; 97: 788-794. 
64. 
Ettinger RA, James EA, Kwok WW, Thompson AR, Pratt DP. Lineages of human T-cell clones, including T helper 17/ 
 
T helper 1 cells, isolated at different stages of anti-factor VIII immune responses. Blood 2009; 114: 1423-1428. 
65. 
Ragni MV. Factor VIII, CD4 and liasions dangereuses. Blood 2011; 117: 6060-6061. 
66. 
Lewis KB, Hughes RJ, Epstein MS. Josephson NC, Kempton CL, Kessler CM, Key NS, Howard TE, Kruse-Jarres R, 
Lusher JM, Walsh CE, Watts RG, Ettinger RA, Pratt KP. Phenotypes of allo- and autoimmune antibody responses 
to FVIII characterized by surface plasmon resonance. PLOS One 2013; 8: e61120. 
67.  
Singer ST, Addiego JE, Reason DC, Lucas AH. T lymphocyte proliferative responses induced by recombinant factor 
VIII in hemophilia A patients with inhibitors. Thromb Haemost 1996; 76: 17-22 
68. 
Reding MT, Wu H, Krampf M, Okita DK, Diethelm-Okita BM, Key NS, Conti-Fine BM. CD4+ T cell response to factor 
VIII in hemophilia A, acquired hemophilia, and healthy subjects. Thromb Haemost 1999; 82: 509-515. 
69. 
Reding MT, Wu H, Krampf M, Okita DK, Diethelm-Okita BM, Christie BA, Key NS, Conti-Fine BM.  Sensitization of 
CD4+ T cells to coagulation factor VIII: response in congenital and acquired hemophilia patients and in healthy 
subjects. Thromb Haemost 2000; 84: 643-652.  
70. 
Reding MT, Wu H, Krampf M, Okita DK, Diethelm-Okita BM, Key NS, Conti-Fine BM. CD4+ T cells specific for factor 
VIII as target for specific suppression of inhibitor production. Adv Exp Med Biol 2001; 489: 119-134.   
71. 
Reding MT, Lei S, Lei H, Green D, Gill J, Conti-Fine BM. Distribution of Th1- and Th2- induced anti-factor VIII IgG 
 
subclasses in congenital and acquired hemophilia patients. Thromb Haemost 2002; 88: 568-575. 
72. 
Ettinger RA, James EA, Kwok WW, Thompson AR, Pratt KP.  HLA-DR restricted T-cell responses to factor VIII 
epitopes  epitopes in a mild haemophilia A family with missense substitution A2201P. Haemophilia 2010; 16: 44-
55. 
73. 
James EA, van Haren SD, Ettinger RA, Fjnvandraat K, Lieerman JA, Kwok WW, Foorberg J, Pratt KP. T-cell responses 
in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site. J 
Thromb Haemost 2011; 9: 689-699. 
74. 
Jacquemin M, Vantomme V, Buhot C, Lavend’homme R, Burny W, Demotte N, Chaux P, Peerlinck K,Vermylen J, 
Maillere B, van der Bruggen P, Saint-Remy JM. CD4+ T-cell clones specific for wild-type factor VIII: a molecular 
mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A. Blood 2003; 
101: 1351-1358. 
75. 
Pratt KP, Qian J, Ellaban E, Okita DK, Diethelm-Okita BM, Conti-Fine B, Scott DW. Immunodominant T-cell epitopes 
 
in the factor VIII C2 domain are located within an inhibitory antibody binding site. Thromb Haemost 2004; 92: 522-
 
528. 
76. 
Ettinger RA, Paz P, James EA, Gunasekera D, Aswad F, Thompson AR, Matthews DC, Pratt KP. T cells from three 
 
hemophilia A subjects recognized the same HLA-restricted FVIII epitope with a narrow TCR repertoire. Blood 2016; 
 
prepublished online July 28; doi 10.1182/blood-2015-11-682-468.  
77. 
Wu H, Reding M, Qian J, Okita DK, Parker E, Lollar P, Hoyer LW, Conti-Fine BM. Mechanism of the 
 
immune response to human factor VIII in murine hemophilia A. Thromb Haemost 2001; 85: 125-133. 
 
78. 
James EA, Kwok WW, Ettinger RA, Thompson AR, Pratt KP.T-cell responses over time in a mild hemophilia A 
 
inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide. J Thromb 
 
Haemost 2007; 5: 2399-2407. 
79. 
Kim YC, Zhang AH, Su Y, Rieder SA, Rossi RJ, Ettinger RA, Pratt KP, Shevach EM, Scott DW. Engineered antigen-
specific human regulatory T cells: immunosuppression of F.VIII-specific T- and B-cell responses. Blood, 2015; 125: 
1107-1115.  
80. 
Medical Product Safety. In Healthy People 2020; 2013:222, MPS-3 http://www.healthypeople.gov/2020. 


 
 
 
 
 
 
 
28
81. 
Gouw SC, Fijnvandraat K. Identifying non-genetic risk factors for inhibitor development in severe hemophilia A.
 
Semin Thromb Haemost 2013; 39: 740-751. 
82. 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, Vol. 4.03, June 
 
14, 2010, http://ctep.cancer.gov/forms/CTCAEv4.pdf 
83. 
Vergruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen 
modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb 
Haemost 1995; 73: 247-251. 
84. 
Miller CH, Platt SJ, Rice AS, Kelly F, Soucie JM. Validation of the Nijmegen-Bethesda assay modifications to allow 
inhibitor measurement during replacement therapy and facilitate inhibitor surveillance. J Thromb Haemost 2012; 
10: 1055-1061. 
85. 
Sahud MA, Pratt KP, Zhukov O, Qu K, Thompson AR. ELISA system for detection of immune responses to FVIII: a 
 
study of 246 samples and correlation with the Bethesda assay. Haemophilia 2007; 13: 317-322. 
86.  
Chauvat A, Benhamouda N, Gey A, Lemoine FM, Paulie S, Carrat F, Gougeon ML, Rozenberg F,Krivine A, Cherai M, 
Lehmann PV,  Quintin-Colonna F, Launay O, Tartour E. Clinical validation of IFNγ/IL-10 and IFNγ/IL-2 fluorospot 
assays for the detection of Tr1 T cells and influenza vaccine monitoring in humans. Hum Vaccines Immunother 
2014; 10: 104-113. 
87. 
Boulet S, Ndongala ML, Peretz Y, Boisvert MP, Boulassel MR, Tremblay C, Routy JP, Sekaly RP, Bernard NF. A dual 
color ELISPOT method for the simultaneous detection of IL-2 and IFN-γ HIV-specific immune responses. J Immunol 
Methods 2007; 320: 18-29. 
88. 
Housseau F, Lindsey KR, Oberholtzer SD, Gonzales MI, Boutin P, Moorthy AK, Shankara S, Roberts Bl, Topalian SL. 
 
Quantitative real-time RT-PCR as a method for monitoring T lymphocyte reactivity to full-length tyrosinase protein 
 
in vaccinated melanoma patients. J Immunol Methods 2002; 266: 87-103. 
89. 
Chaussabel D, Baldwin N. Democratizing systems immunology with modular transcriptional repertoire 
 
analyses. Nat Rev Immunol 2014; 14: 271-280. 
90. 
Pratt KP, Thompson AR. B-cell and T-cell epitopes in anti-factor VIII immune responses. Clin Rev Allergy Immunol 
2009; 37: 80-95. 
91. 
Gunasekera D, Dutta DK, James EA, Ragni MV, Pratt KP. PBMCs from hemophilia A subjects show robust cytokine 
 
secretion in response to factor VIII C2 domain epitopes. Blood 2015: 126; 2291  (abstract). 
92. 
Sommer JM, Moore N, McGuffie-Valentine B, Bardan S, Buyue Y, Kamphaus GD, Konkle BA, Pierce GF. Comparative 
field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical 
haemostasis laboratories. Haemophilia 2014; 20:194-300. 
93. 
Oldenburg J. Mutation profiling in haemophilia A. Thromb Haemost 2001; 85: 577-579. 
94. 
Rosetti LC, Radic CP, Larripa IB, De Brasi CD. Developing a new generation of tests for genotyping hemophilia - 
causative rearrangements involving int22h and int1h hotspots in the factor VIII gene. J Thromb Haemost 2008; 6: 
830-836. 
95. 
PROC POWER, SASS/STAT software, version 9.3. SAS Institute Inc., Cary North Carolina.  
96. 
Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emizumab prophylaxis in hemophilia A without inhibitors. N Engl J Med 
 
2018; 379: 811-812. 
97.  
Kitazawa T, Igawa T, Sampei Z, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic 
activity in a hemophilia A model. Nat Med 2012; 18: 1570-1576. 
98.  
Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against 
ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 2014; 
12: 206-213. 
99.  
Muto A, Yoshihashi K, Takeda M, et al. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-
term primate model of acquired hemophilia A. Blood 2014;124:3165-711.  
100.  
Shima M, Hanabusa H, Taki M, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia 
A. N Engl J Med 2016; 374: 2044-2053. 
101.  
Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. New Engl J Med 
2017; 377: 809-828. 
102.  
Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: 
how does it actually compare to factor VIII? Blood 2017; 130: 2463-2468. 


 
 
 
 
 
 
 
29
103.  
van Vulpen LFD, Schutgens REG, Coeleveld K, et al. IL-1ß, in contrast to TNFa, is pivotal in blood-induced cartilage 
damage and is a potential target for therapy. Blood 2015; 126: 2239-2246. 
104.  
Institute for Clinical & Economic Review. Emicizumab for Hemophilia A with Inhibitors: Effectiveness and Value. 
Evidence Report. March 15, 2018. ICER Review, 2018. 
105.  
Konkle BA, Shapiro A, Quon DV, Staber JM, Suzuki T, Kulkarni R, Ragni MV, Poloskey S, Rice K, Katragadda S, Rudin 
D, Fruebis J. BIVV001: The first investigational factor VIII (FVIII) therapy to break through the von Willebrand factor 
(VWD) ceiling, with potential for more optimal, extended protection in hemophilia A. ISTH International Society 
of Hematology, July 6-10, Melbourne Australia, abstract. 
106. 
Ragni MV, George LA. The National Blueprint for Future Factor VIII Inhibitor Clinical Trials: NHLBI State of the 
Science (SOS) Workshop on Factor VIII Inhibitors. Scientific Priorities and Innovative Implementation Strategies 
for FVIII Inhibitor Clinical Trials: NHLBI State of the Science Workshop Working Group-1. On behalf of Members of 
Working Group 1. Haemophilia 2019; doi:10.1111/hae.13717 
107. 
Ragni MV, Moore CG, Bias V, Key NS, Kouides PA, Francis CW. Challenges of rare disease research: limited patients 
and competing priorities. Haemophilia 2012; 18: 192-194. 
108. 
Iorio A, Marcucci M. Clinical trials and haemophilia: does the Bayesian approach make the ideal and desirable 
good friend? Haemophilia 2009; 15: 900-903. 
109. 
Peyvandi F, Farrugia A, Iorio A, Key NS, Srivastava A. Joint WFH-ISTH session: issues in clinical trial design. 
Haemophilia 2014; 20 Suppl 4: 137-144. 
110. 
Cheng J, Iorio A, Marcucci M, et al. Bayesian approach to the assessment of the population-specific risk of 
inhibitors in hemophilia A patients: a case study. J Blood Med 2016; 7: 239-253. 
111. 
Ragni MV, Kessler CM, Fogarty PJ, Josephson NC, Neff AT, Raffini LJ. Survey of current prophylaxis practice in U.S. 
hemophilia treatment centers. Haemophilia 2012; 18:63-68.  
112. 
Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia 
A with inhibitors. New Engl J Med 2017; 377: 809-818 
113. 
Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al. Emizumab prophylaxis in hemophilia 
A without inhibitors. N Engl J Med 2018; 379; 811-822. 
114. 
The National Blueprint for Future Basic and Translational Research to Understand Factor VIII Immunogenicity: 
NHLBI State of the Science (SOS) Workshop on Factor VIII Inhibitors. Shannon L. Meeks and Roland W. Herzog on 
behalf of the Members of Working Group 3, The NHLBI State of the Science Workshop on Factor VIII Inhibitors: 
Generating a National Blueprint for Future Research. Haemophilia 2019; 
115. 
DiMichele DM. Ethical considerations in clinical investigation: exploring relevance in haemophilia research. 
Haemophilia 208; 14 (Suppl 3): 122-129. 
116. 
Berry DA. Emerging innovations in clinical trial design. Clin Pharm & Therapeutics 2016; 99: 82-91. 
117. 
Viele K, Berry S, Neuenschwander B, Amzal B, Chen F, Enas N, et al. Use of historical control data for assessing 
treatment effects in clinical trials. Pharm Stat 2014; 13: 41-54. 
118. 
Redman MW, Allegra CJ. The master protocol concept. Sem Oncol 2015; 42: 724-730. 
119. 
Newman AB, Avilés ML, Anderson G, Heiss G, Howard WJ, Krucoff M, et al. Embedding clinical interventions into 
observational studies. Contemp Clin Trials 2016; 46: 100-105. 
 
120.   
Nathwani AC, Reiss UM, Tuddenheim EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy 
of factor IX gene therapy in hemophilia B. N Engl J Med 2011; 371: 1994-2004.  
121. 
George LA, Sullivan SK, Giermasz A, Ducore J, Rasko J, Samelson-Jones BJ, et al. Endogenous prophylaxis for 
hemophilia B following gene therapy with a high specific factor IX variant. N Engl J Med 2017; 377: 2215-2227. 
122. 
Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe 
hemophilia A. N Engl J Med 2017; 377:2519-2530. 
123. 
Finn JD, Ozelo MC, Sabatino DE, Franck HWG, Merricks E, Crudele JM, et al.  Eradication of neutralizing antibodies 
to factor VIII in canine hemophilia A after liver gene therapy. Blood 2010; 116: 5842-5848. 
124. 
El-Enein M, Grainger DW, Kili S. Registry contributions to strengthen cell and gene therapeutic evidence. Molecular 
Therapy 2018; 26: 1172-1176. 
125.      Ragni MV, Malec LM. Design of the INHIBIT trial: Preventing inhibitors by avoiding “danger,” prolonging half-life, 
and promoting tolerance. Expert Reviews Hematology 2014; 7: 747-755. 
126. 
Wight J and Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 
418–35.  


 
 
 
 
 
 
 
30
127. 
De Boeck K, Bulteel V Fajac I. Disease-specific clinical trials networks: the example of cystic fibrosis. Eur J Pediatr 
2016; 175: 817-824. 
 
128.  
The National Blueprint for Future Clinical Research for 21st Century Data and Bio-Specimen Collection: NHLBI State 
of the Science (SOS) Workshop on Factor VIII Inhibitors. Barbara A. Konkle and Michael R. Recht, on behalf of the 
Members of Working Group 2, The NHLBI State of the Science Workshop on Factor VIII Inhibitors: Generating a 
National Blueprint for Future Research. Haemophilia 2018; 
129. 
Extramural 
Nexus: 
The 
roles 
of 
fellows 
and 
trainees 
in 
NIH-supported 
trials.  
https://nexus.od.nih.gov/all/2018/10/12/the-roles-of-fellows-and-trainees-in-nih-supportedclinical-trials/. 
130. 
Young G. Implementing emicizumab in hemophilia inhibitor management: emicizumab should be prescribed after 
tolerance. Blood Advances 2018; 2: 2780-2782. 
131. 
Le Quellec S, Negrier C. Emicizumab should be prescribed independent of immune tolerance induction. Blood 
Advances 2018; 2: 2783-2786. 
132. 
Königs C, Liesner R, Ozelo MC, Shapiro AD, Brown SA, Innes A, Winding B, Reuter C, Rudin D, Carcao M. Incidence 
of inhibitors in previously untreated patients with severe hemophilia A treated with rFVIIIFc: The PUPSs A-LONG 
study. Haemophilia 2019; 25 (Suppl 1): OR 14. 
133. 
van den Berg M, Kurnik K, Ljung R, Male C, Kenet G Carcao M, Chambost H Fischer K, Oldenburg J, Alvarez Roman 
MT, Santagostino E, Konigs C, Williams M, Lienser R, Ortiz AS, Buhrlen M, Andersson NG Carvalho M, Makipernaa 
A Chalmers E, Molinari AC Nolan B Cid AR, Claeyssens S Platokouki H, Rafowicz A, Escuiola C, Ranta S, Rivard G, 
Glosli H, Mikkelsen TS Kobelt R, van Geet C. Until what age should we worry about inhibitors? New data from the 
Pednet Registry on 1,038 PUPs with severe hemophilia A followed from the first until over 1,000 exposure days. 
Haemophilia 2019; 25 (Suppl 1): OR 05. 
134. 
Königs C, Liesner R, Ozelo MC, Shapiro AD, Brown SA, Innes A, Winding B, Reuter C Rudin D, Carcao M. Incidence 
of inhibitors in previously untreated patients with severe haemophilia A treated with rFVIIIFc: The PUPs A-LONG 
study. Haemophilia 2019; 24 (Suppl 1): OR14. 
135. 
Carcao M, Shapiro A, Staber JM, Hwang N Druzgal C, Lieuw K, Belletrutti M, Thornburg CD, Ahuja SP, Morales-
Arias J, Dumont J, Miyasato G, Tsao E, Jain N, Pipe SW. Recombinant factor VIII Fc fusion protein for immune 
tolerance induction in patients with severe haemophilia A with inhibitors – A retrospective analysis. Haemophila 
2018; 24: 245-252 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
31
 
APPENDIX 
 
Schedule of Events 
 
*Genotype, HLA are on buffy coat; **FVIII chromogenic is on aliquot of anti-FVIII; **ELISPOT is after 5 exposure days, in lieu of wk 12 or 24, if closer. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table  
Schedule of Events 
 
Study Week                         
Week 
0 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Screening, consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Initiate study arms 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Initiate study diary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End-of-study visit 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-FVIII NBU chromogenic 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Hemophilia genotype* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HLA type* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FVIII chromogenic (trough)* 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
T cell (ELISPOT, Ig, RNA)** 
X 
X 
 
X** 
 
 
X** 
 
 
X 
 
 
X 
Microbiome sample  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for storage 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 


 
 
 
 
 
 
 
32
Summary of changes from 07-01-20 to 08-08-20  
Protocol v1.0 
 
1. Page 1. A front page with the INHIBIT Logo, protocol number and NCT number and other identifying 
information was added to page 1. 
2. Page 2. A one-page summary of the protocol was added on page 2. 
3. Page 3. Typeset was changed to Calibri Body 11 font, with margin justification throughout, and 
pagination was switched for ease to the right lower border. 
4. Page 3. Abstract, lines 1, 2: Specific drugs to be compared are now included. 
5. Page 4-6. Secondary endpoints were revised to specify a precise endpoint, CNS bleed, rather than life-
threatening bleed, and use of phrase inhibitor formation rather than term, inhibitor-free, for consistency 
throughout the protocol, data forms; and redundant phrases were removed. 
6. Page 7. The word “caretaker” is now used consistently throughout the protocol. 
7. Page 8. Clarifications were made in wording, grammar, terminology for consistency throughout the 
protocol. Protocol team discussions agreed that up to three bleeds would be allowed, including 
circumcision, as otherwise impractical to enroll on study. 
8. Page 8. The protocol team clarified the primary and secondary endpoints that are now consistent 
throughout the protocol, including the inclusion of patients if they had no more than 3 FVIII exposures 
(including FVIII in concentrate, cryoprecipitate, or fresh frozen plasma), including circumcision. This is 
standardly used in PUP protocols and acknowledges how difficult it is to enroll PUPs on trials with no 
previous exposure. Up to three exposures is generally viewed as not having impact on inhibitor 
occurrence. 
9. Page 9. Visits were labeled to assure accurate reflection of visit events. Dimethyl sulfoxide is correctly 
abbreviated “DMSO” for PBMC studies throughout the protocol. 
10. Page 13. The table was resized to read more easily. For consistency, patients who will enroll will be age 
> 4 months up to 4 years, and is specified throughout the protocol, including inclusion criteria, Section 
3.5 and 4.3 (below). The reasons a subject might be unsuitable are now consistently listed in the 
exclusion criteria only. 
11. Page 13-14. Details of the primary and secondary endpoints are now clarified with input of statisticians 
on the protocol team. 
12. Page 15. Section 4.3 is revised as stated above for Section 3.5 (see 10. above). A sentence was added 
regarding data capture, electronic data forms, and management. 
13. Page 16. The terms site (HTC), randomization, and random assignment, and assigned treatment are 
clarified. 
14. Page 19. Members of the Data Safety Monitoring Board (DSMB) are now more explicitly listed by 
expertise in hematology, hemophilia, and statistics, all with voting rights. 
15. Page 23. Qualifications of investigators: Since Debbie Vehec has joined as the main clinical nurse 
coordinator, to take the place of Julie Sheline who has left the center. 
 
 
Summary of changes to 10-05-20 protocol (clarification) 
Protocol v2.0 
1. Minor corrections and clarifications throughout protocol 
2. Adaptive design updated to Bayesian platform design throughout protocol 
3. Page 1.  Protocol Version and date updated 
4. Page 2.  Endpoints: updated to include microbiome stool sample 
5. Page 4.  Objective and Specific Aims: Addition of microbiome stool sample 
6. Page 6.  Specific Aim 2: Addition of microbiome stool sample 
7. Page 8.  Screening Period: Addition of microbiome stool sample 
8. Page 12. Study population: clarified exclusion: if current use of Emicizumab, known start date 
9. Page 15. Exclusion criteria: if current use of Emicizumab, known start date 


 
 
 
 
 
 
 
33
Summary of changes to 02-26-21 protocol (clarification) 
Protocol v3.0  
• 
Page 10. Study Visits 3, 5, 6, 8, 9, 11, 12:  Monthly Follow-up Visits: Added Can be done remotely or in 
person and removed: Vital signs [blood pressure (BP), pulse (P), respiratory rate (RR), and oral 
temperature (ºC)] will be taken, and weight (kg) will be obtained. 
 

ICF_002.pdf: 
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<INSERT LOCAL LETTERHEAD>
 
CONSENT FOR A CHILD TO ACT AS SUBJECT IN A RESEARCH STUDY
(Subjects 4 months to 4 years old)
Protocol Title: The Phase III Multicenter, Randomized, Controlled Inhibitor Prevention Trial, 
comparing Eloctate (rFVIIIFc) vs. Emicizumab (Hemlibra) to Prevent Inhibitor Formation in 
Severe Hemophilia A
PRINCIPAL INVESTIGATOR: 
<INSERT LOCAL PI>
CO-INVESTIGATORS:
<INSERT LOCAL CO-INVESTIGATORS> 
 
SOURCE OF SUPPORT:  HRSA, Health Resources Services Administration 
Consent Version: 
v3.0  08 June 2021
   
Key Information:  Your child is being asked to take part in a research study. Your child’s 
participation is voluntary. The study team members will explain the study to you/ your child and 
answer any questions you/ your child may have. You/your child should take time to make your 
decision. 

Purpose of Research: The purpose of this research is to prevent inhibitor formation in 
severe hemophilia A patients.

Randomization: There is a 3 in 4 chance of being randomized to Emicizumab and 1 in 4 
chance of being randomized to Eloctate.

Specimen Collection and storage: Blood draws will be collected at 6 time points: 
baseline, 4, 12, 24, 36, and 48 weeks; samples will be frozen and stored indefinitely.

Collection of Medical Record Information and subject diary: Data collected will 
include demographics, hemophilia diagnosis, bleeding history, and medication used for 
bleeds. A diary will record the date and time of bleeds, and the medication used for 
bleeds and other medications, including date, time, and amount. A stool sample will be 
collected at baseline.

Risks of Study: The likely risks associated with this study include lightheadedness, 
bruising or bleeding from a blood draw, risk of minor pain, bleeding, or bruising 
following drug administration, allergic reaction to a study drug(s), risk of inhibitor 
formation, risk of blood clots, and the risk of breach of confidentiality of your health 
information.

Benefit of Study: You may benefit from participating in this study, as these study drugs 
may reduce bleeds; however, there is no guarantee.

Alternate Procedures: If you/your child decide not to participate, there are other choices 
for care and treatment without being in a study.


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Why is this research being done?  
Your child is being asked to participate in this research study to prevent inhibitors (antibodies to 
infused factor VIII) in severe hemophilia A. Hemophilia A is an inherited (genetic) disease in 
which a protein (factor VIII, FVIII) that stops bleeding by making a blood clot, is missing or 
does not work properly. Individuals with severe hemophilia A have less than 1% of the normal 
clotting FVIII and have bleeds with trauma or without trauma (spontaneous). Current treatment 
for hemophilia A is by infusing the missing clotting FVIII into a vein. To prevent spontaneous 
bleeding in patients with severe hemophilia A, doctors recommend regularly scheduled doses of 
FVIII called “prophylaxis”. However, in up to 30% of patients who receive factor VIII, an 
“inhibitor” can form. Inhibitors are proteins or antibodies made by the immune system against 
infused factor VIII because it looks “foreign” or different from your own FVIII. These inhibitor 
antibodies prevent standard clotting factor VIII from working properly. If an inhibitor occurs, 
treatment is by “bypass therapy” (VIIa or activated IX (aPCC)), but bleeds are poorly controlled 
with these agents. As a result, patients with inhibitors have more hospitalizations and 
complications than those without inhibitors. At this time, it is not known how to prevent 
inhibitors. Thus, a major goal of hemophilia treatment is to prevent inhibitors. 
Two FDA-approved drugs will be studied in the proposed trials. These include 1) Eloctate 
(rFVIIIFc) or recombinant factor VIII Fc fusion protein, and 2) Emicizumab (Hemlibra), the 
bispecific monoclonal antibody that is a FVIII mimic. Eloctate increases the half-life (duration) 
of FVIII in the circulation, and, in small studies, may reduce the rate of inhibitor formation and 
shorten ITI (immune tolerance induction, i.e. inhibitor eradication) in inhibitor patients, even 
those resistant to ITI. Eloctate is safe and effective in preventing bleeds in adults, adolescents, 
and children. The bispecific monoclonal antibody, Emicizumab, is a FVIII mimic, substituting 
for missing or inhibited FVIII in the coagulation pathway, and in clinical trials has been safe and 
effective in preventing bleeds in adults, adolescents, and children with severe hemophilia A with 
and without inhibitors.
This Inhibitor Prevention Trial is a 48-week phase III trial. We will enroll children with severe 
hemophilia A who have not been previously treated (except for circumcision). We will compare 
Emicizumab with Eloctate in the prevention of inhibitors in children before they have a bleed or 
surgery or trauma (preemptive) and continued weekly to prevent bleeds (prophylaxis).  
Who is being asked to take part in this research study?
Children with severe hemophilia A, 4 months of age or older, who have received three or fewer 
FVIII treatments for a bleed cared for at the <INSERT LOCAL SITE> will be recruited for this 
study. 
What procedures will be performed for research purposes?
 This is a 48-week outpatient study with approximately 13 study visits which include screening, 
follow-up, and end of study visits. The study involves two FDA-approved drugs; one is given IV 
(intravenously – injection directly into the vein) and one given SQ (subcutaneously – injection 
under the skin). 


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If you agree for your child to participate in this study, he will be screened for eligibility. If he is 
eligible, he will receive one of two treatment. Blood draws will be performed at 6 timepoints: 
baseline, 4, 12, 24, 36, and 48 weeks. Follow-up visits will be conducted monthly to the end of 
the study.
SCREENING VISIT & ENROLLMENT
Study Visit 1: Screening
If you agree for your child to participate in this study and sign the informed consent, the study 
staff will complete the following screening procedures (below) within 24 hours of enrollment. 

Study staff will collect age, date of birth, race, and hemophilia genotype.

Study staff will ask about your child’s medical history: height, weight, past factor 
treatment, dose and frequency, and past circumcision and bleeding.

Hemophilia history and previous FVIII treatment.

Medication in the last 4 weeks.

Brief physical exam with vital signs, height (cm) and weight (kg).

Blood draw: Your child will have a ¾ tsp sample drawn for FVIII, inhibitor, immunity, 
genotype, and a sample stored for future related studies.

A stool sample will be collected at baseline (may be collected at home and mailed back 
into the Hemophilia Center of Western Pennsylvania {Coordinating Center}) to assess 
genes and bacteria in the gut (microbiome).
Enrollment 
After the doctor determines your child can participate, he will begin the study drug. He will take 
it preferably between 7 am and 9 am weekly during the study.
Your child will receive one of two drugs: either Eloctate at 65 IU/kg IVweekly or Emicizumab 
1.5 mg/kg SQ (after a 4-week induction at 3 mg/kg/week SQ) as part of his regular care. The 
drug will begin before the first bleed and continue weekly during the 48-week study. Your child 
will have a 3 out of 4 chance of receiving Emicizumab or 1 out of 4 chance receiving Eloctate.  
Which drug your child receives is determined by randomization process, like rolling dice. 
Subjects will use their own supply of Eloctate or Emicizumab. The dose used in this study is the 
same dose used in standard care. 

Your child will use his own supply of study drug. Your child will be assigned to receive 
either Eloctate or Emicizumab. If he receives Eloctate, it will be given IV (through a 
vein) using an infusion needle (butterfly) or by central line. If he receives Emicizumab, it 
will be given SQ (under the skin injection), depending on the study drug to which your 
child is assigned. You will decided with the nurse at the Hemophilia Center where your 
child’s study drug will be given. If you have learned infusion or injection techniques and 
are certified by your <INSERT LOCAL SITE>, you may give the drug at home. If your 
child has breakthrough bleeds, your child’s physician will discuss treatment and if a 
central line is needed, but it should not change where your child receives the study drug. 


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
All doses of study drug will be given either by venipuncture, using a butterfly or central 
line if required, or by subcutaneous injection and take about 5-10 minutes.

You will record all doses of study drug that your child takes (date, time, dose) in a patient 
diary which the study nurse will give you. You should bring it to all study visits to review 
with the nurse.

If your child is currently being treated with Emicizumab, you will be asked to discontinue 
the drug prior to randomization. If you are unwilling to discontinue Emicizumab 
treatment prior to randomization, you will no longer be eligible to participate in this 
study.
The nurse will discuss study visits with you. The visit will take 1 hour. 
If your child has a bleed, Eloctate will be given, similar to standard care, and whether your child 
is assigned to receive Eloctate or Emicizumab. That is because Emicizumab prevents, but does 
not treat, bleeds.  After the bleed resolves, your child’s physician will discuss with you whether 
to treat more frequently with Eloctate for bleeds, similar to standard care. Only Eloctate or 
Emicizumab may be used during the study, and your child should only use the study drug to 
which he is assigned, unless an inhibitor develops (see below). You will be responsible to work 
with the nurse to assure your child has enough study drug(s) at all times. 
If your child develops an inhibitor, a repeat blood testing must be drawn within 4 weeks to 
confirm it. If confirmed, your child’s physician will decide with you the best treatment for your 
child.  Even if your child stops the study drug, he will remain on study for collection of 
information and follow up until the end of the study (48 weeks). If at the time of inhibitor 
detection, your child has no bleeding, then there will be no change in study drug until the second 
blood test confirms the inhibitor (within 4 weeks): at that time your child’s doctor will decide 
with you the best treatment for your child. If an inhibitor develops and bleeding does not respond 
to study drug, then even before the inhibitor is confirmed, your child may stop study drug and 
receive treatment, but he will be followed until week 48. At no time will activated FIX (aPCCs) 
be allowed on this trial because of potential thrombosis with recent emicizumab use.  The 
schedule and procedures are outlined below and in the Appendix of this consent form. Please 
note: if your child develops an inhibitor on the trial, he may be invited to join the linked 
“Inhibitor Eradication Trial.” Your child’s doctor will discuss this with you.
FOLLOW-UP VISITS:
At follow-up visits, you will review your child’s supply of study drug with the study nurse who 
will help order more doses to assure you have enough until the next visit. You will need to 
record all your child’s bleeds and medicines on the Subject Diary. The first dose may be given 
on the day of screening, or as soon as the prescription is filled.  Follow up visits will be monthly  
at <INSERT LOCAL SITE> at 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 weeks.  
Study Visit 2: Week 4, Follow-up Visit


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
Your child’s diary will be reviewed for bleeds and the date, time and dose study drug was 
given, other medications given, and any complications.

Study drug use will be reviewed and more ordered as needed.

Vital signs will be taken, and weight will be obtained.

A ¾ tsp blood sample will be drawn for inhibitor, FVIII, immune studies, and a sample 
stored for future studies. All samples must be drawn before the study drug is given.
Study Visits 3, 5, 6, 8, 9, 11, 12: Monthly Follow-up Visits (Can be done remotely or in person)

Your child’s diary will be reviewed for bleeds and date, time and dose of study drug.

More study drug will be ordered as needed.

All medications will be recorded and reviewed.

Assessment for adverse events (complications) will be completed.
Study Visit 4, 7, 10:  Quarterly Follow-up Visit

Your child’s diary will be reviewed for bleeds and date, time and dose of study drug.

More study drug will be ordered as needed.

All medications will be recorded and reviewed.

Assessment for adverse events (complications) will be completed.

Vital signs and weight will be obtained.

A ¾ tsp blood sample will be drawn for for inhibitor, FVIII, immune studies, and a 
sample stored for future studies. All samples must be drawn before the study drug is 
given.
END-OF-STUDY VISIT:
Study Visit 13: Week 48, End-of-Study Visit

Your child’s diary will be reviewed for bleeds and date, time and dose of study drug.

More study drug will be ordered as needed.

All medications will be recorded and reviewed.

Assessment for adverse events (complications) will be completed.

Vital signs and weight will be obtained.

A ¾ tsp blood sample will be drawn for for inhibitor, FVIII, immune studies, and a 
sample stored for future studies. All samples must be drawn before the study drug is 
given.
The total blood draw during the study is 4½ tsp. The blood draw will be less for children 
weighing less than 14 pounds. (See the Appendix, last page). The blood samples will be de-
identified (no name) and sent to the Hemostasis Laboratory, Puget Sound Blood Center, Seattle 
WA, and to the Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD.
What are the possible risks, side effects, and discomforts of this research study?
As with any study drug, there may be side effects that are currently unknown, and it is possible 
these could be permanent, serious, or life threatening. This study involves study drug Eloctate or 


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Emicizumab, each approved by the FDA for the prevention of bleeds for hemophilia. Each drug 
has been shown safe and effective in adults and children and are used as part of standard care. It 
is not known whether either study drug will prevent inhibitor formation in individuals with 
severe hemophilia A.
You should talk to the study doctor or your child’s regular doctor about the potential risks. Every 
effort will be made to reduce these risks. There are risks associated with receiving the study drug 
and having blood drawn. You will be asked to report any safety problems or side effects 
associated with administration of study drug, whether given at <INSERT LOCAL SITE>, 
infusion center, or at home.
Discontinuing Emicizumab prior to randomization
There are no known risks associated with discontinuing Emicizumab. If a bleed occurs, factor 
VIII will be given until it resolves and monitored by your child’s doctor.
Eloctate
Common risks include malaise (feeling unwell) and joint aching in 2% (2 per 100 people); and in 
1% (1 per 100 people) feeling hot or cold, dizziness, unusual taste, headache, joint swelling, 
muscle pain, abdominal discomfort, blood vessel disease, high blood pressure, slow heart rate, 
skin rash, and cough.  
Emicizumab
Common risks include injection site reactions, headache, and arthralgia (joint pain).
Inhibitor Development  
Inhibitor development occurs in 28-30% of individuals with severe hemophilia A (factor VIII 
deficiency). Among those who develop inhibitors 95% or more occur within 50 exposure days, 
usually in childhood after 10-20 exposure days, by the age of 2. Currently there is no known way 
to prevent inhibitor formation. Your child will be followed closely to monitor this risk, and 
samples to detect inhibitors will be taken at several time points in the study to monitor for this 
possibility. Should an inhibitor occur, treatment with factor VIIa (rFVIIa) will be determined at 
the discretion of your child’s physician. No children with a past history of bleeding or inhibitors 
will be enrolled on this study. 
Allergic or Anaphylactic Reaction 
Allergic type reactions including anaphylaxis have only rarely, <0.001%, or less than 1 per 
100,000 people, been reported for factor VIII and other hemostatic drugs. Symptoms could 
include hives, rash, swelling, chest tightness, shortness of breath, wheezing, faintness, low blood 
pressure, rapid heartbeat, and anaphylaxis (a life-threatening condition). If this occurs, the 
infusion should be stopped, and you should contact us immediately. If your child’s symptoms are 
severe, call 911. Your child should receive immediate treatment. Should these symptoms occur, 
Benadryl, a medication which reduces inflammation, or an epi-pen, which improves vessel tone 
and lung function, may be given, with close monitoring of symptoms. Benadryl may cause 


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drowsiness, dizziness or low blood pressure; an epi-pen may cause rapid heart rate, sweating, 
nausea, or anxiety. Your child will be monitored for these symptoms after receiving this drug. 
No one with a history of allergy to FVIII will be enrolled in these trials.
Thromboembolism/Thrombogenicity
Historically factor VIII products and other hemostatic agents are rarely, if ever, associated with 
the development of thromboembolic complications (blood clots). None have been detected in 
any of the studies of Emicizumab or Eloctate in adults or children, except rarely when activated 
factor IX (aPCCs) are taken with Emicizumab, < 0.01% or less than 1 per 100 people. For that 
reason, aPCCs will not be allowed on this trial.  There is the unlikely possibility, < 0.001%, or 
less than 1 per 100,000 people, that these drugs (in the absence of aPCCs) could cause a clot, 
swelling, or inflammation in a vein. This risk will be very carefully monitored clinically. Should 
these symptoms occur in your child, you should contact us immediately, or if the symptoms are 
severe, measures considered standard of care, including stopping the study treatment and/or 
removing the line in which it was given, if that is the source of the clot, should be done as soon 
as possible. 
Bleeding Events
Because your child has hemophilia, there is an additional risk of bleeding at the infusion site. 
Contact us if this occurs and seek medical attention. In the event that bleeding at the infusion site 
cannot be stopped with pressure, it may be necessary to use a stitch or an adhesive material to 
stop the bleeding. The devices used to administer the stitch or adhesive may cause the following 
negative side effects: bleeding, a build-up of blood known as a hematoma, infection, allergic 
reaction, nerve injury, and swelling.  
Venipuncture 
There may be discomfort with drawing your child’s blood, which is common, occurring in up to 
25%, or 25 in 100 people: this may include pain, lightheadedness, fainting, bruising, or bleeding 
or infection in the tissue around the vein.  This may be alleviated or reduced by applying 
pressure to the blood draw site for 5 minutes and having your child lie on his back. The risk of 
repeated blood draws is anemia, or a low blood count, but this will be carefully monitored. 
Injections may rarely, in less than 1%, or less than 1 in 100 people, cause pain, soreness, redness, 
warmth, itching, numbness, tenderness, swelling, skin changes (discoloration, breakdown, or 
thickening), or swelling or lymph nodes near the injection site. 
IV Placement
There may be discomfort during IV placement. Insertion of an IV line is typically a minimal risk 
procedure. However, taking blood or putting and intravenous catheter in people with hemophilia 
may increase chance of pain, bleeding or bruising at the spot where the needle enters your body, 
lightheadedness or fainting, swelling and redness at needle site, infection, or inflammation of 
vein. Emla cream (a skin-numbing medicine) may be used to minimize this discomfort.
Subcutaneous Injection


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Subjects could develop a reaction at the site of the injection, which could include pain, 
tenderness, redness, swelling, itching, sores, skin color changes, or other reactions around the 
injection site.
Central Line Placement
In young children, difficulty obtaining venous access due to small veins may require the 
placement of a central line. The insertion of a central line may reduce the discomfort of needle 
sticks and will be suggested at the discretion of the treating physician. Placement of central lines 
may cause bleeding, and thus additional factor treatment may be necessary. There is also the risk 
of anesthesia required for the line placement procedure. In addition, central lines may be 
complicated by infections that require hospitalization, antibiotics, and/or removal and 
replacement of the line. The insertion of a central line is part of clinical care and not required for 
this study.  Placement of a central line could lead to an infection or pneumothorax (collapsed 
lung). 
Stool Collection
There are no known risks of stool sample collection
Collection of Medical Information and Subject Diary                                                                                             
Study participation and related data will be protected to maintain confidentiality.  There is a 
possibility that your child’s personal information could become generally known. In order to 
reduce risks of disclosure or breach of confidentiality, the research related documents, blood 
samples and clinical information stored in your child’s research files will be assigned an 
alphanumeric (letters and numbers) identifier (that do not contain personal identifiers). A linkage 
key for linking this number and your or your child’s name will be kept at <INSERT LOCAL 
SITE> under lock and key by the <INSERT LOCAL SITE> research staff.  Any publication 
arising from this study will not contain names or other identification unless you give permission 
in another signed consent.   
Future Genetic Testing of Stored Samples
There is the possibility that if the results of the research studies involving your child’s genetic 
material were to become generally known, this information could affect your or your child’s 
ability to be insured, employed, or influence plans for children or have a negative impact on 
family relationships, and/or result in paternity suits or stigmatization. 
In addition, there is a Federal law, called the Genetic Information Nondiscrimination Act 
(GINA), that generally makes it illegal for health insurance companies and group health plans to 
use genetic information in making decisions regarding your eligibility or premiums. GINA also 
makes it illegal for employers with 15 or more employees to use your genetic information when 
making decisions regarding hiring, promoting, firing, or setting the terms of employment. This 
new Federal law does not protect you against genetic discrimination by companies that sell life, 
disability, or long-term care insurance.


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Your research data/samples may be shared with investigators conducting other research; this 
information will be shared without identifiable information.  These research data/samples may 
contribute to a new discovery or treatment.  In some instances, these discoveries or treatments 
may be of commercial value and may be sold, patented, or licensed by the investigators and the 
University of Pittsburgh for use in other research or the development of new products.  You will 
not retain any property rights, nor will you share in any money that the investigators, the 
University of Pittsburgh, or their agents may realize.
The data, samples, and genetic data generated from samples may be shared with other 
researchers and with federal repositories, in a de-identified manner without additional informed 
consent.
What are possible benefits from taking part in this study?
Currently there are no agents to prevent inhibitors. Your child could benefit if the study finds 
that any of the study drug(s) will prevent inhibitors in severe hemophilia A subjects. This could 
improve quality of life and decrease or prevent costs associated with inhibitor development or 
eradication. However, it is important to note that your child may not receive direct benefit from 
taking part in this research study and the only benefit may be that information obtained from 
your child’s participation may help others in the future.
Will my child receive any results from taking part in this study?
The results of inhibitor testing will be provided to you during the study.
What treatments or procedures are available if my child should not take part in this research 
study?
There are no known cures for those with hemophilia and inhibitors. Other alternative factor 
treatments (recombinant factor VIII, rFVIII for hemophilia, or rFVIIa for inhibitors) are 
available to your child to treat or prevent bleeds. 
If my child agrees to take part in this research study, will my child be told of any new risks that 
may be found during the course of the study?
You will be promptly notified if, during the conduct of this research study, any new information 
develops which may cause you to change your mind about continuing to participate.
Will my insurance provider or I be charged for the costs of any procedures performed as part 
of this research study?
Neither you, nor your insurance provider, will be charged for the costs of any of the procedures 
performed for the purpose of this research study (i.e., the Screening Procedures, Monitoring, and 
End of Study visits described above).  Neither the study nor the sponsor of the study will provide 
the Eloctate or Emicizumab as you will be using your own supply of drug. Should your child’s 
physician recommend central line placement, the costs will not be covered by this research study.


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Will I be paid if I or my child takes part in this research study?
<INSERT LOCAL COMPENSATION>
Who will pay if my child is injured as a result of taking part in this study?
<INSERT LOCAL COMPENSATION FOR INJURY LANGUAGE>
Who will know about my child’s participation in this research study?
Any information about your child obtained from this research will be kept as confidential 
(private) as possible.  All records related to your or your child’s involvement in this research 
study will be stored in a locked file cabinet. Your child’s identity on these records will be 
indicated by a case number rather than by your child’s name, and the information linking these 
case numbers with your child’s identity will be kept separate from the research records. De-
identified information will also be stored in a secure database. The web-based data base is 
located at the Data Coordinating Center, Graduate School of Public Health, University of 
Pittsburgh. Your child will not be identified by name in any publication of the research results 
unless you sign a separate consent form giving your permission (release).
In addition to the investigators listed and their research staff, the following individuals may have 
access to your information related to your participation in this research study:

Authorized representatives of the study sponsor, federal regulatory agencies, the Data 
Safety and Monitoring Board (DSMB) and the University of Pittsburgh Office of 
Research Protections may review your identifiable research information for purposes of 
monitoring the conduct of this research study. 

Information collected from this study may be shared with other investigators; however, 
this information will be shared in a de-identified manner (i.e., without identifiers).

De-identified blood samples in this study will be sent to the Hemostasis Laboratory, 
Puget Sound Blood Center, Seattle WA, and to the Uniformed Services University of the 
Health Sciences (USUHS), Bethesda, MD. 

If the investigators learn that your child or someone with whom your child is involved is 
in serious danger or potential harm, they will need to inform, as required by <INSERT 
LOCAL STATE> law, the appropriate agencies.

<INSERT ANY LOCAL ENTITIES>
<INSERT LOCAL DATA RETENTION PERIOD LANGUAGE>
HIPAA Authorization for Disclosure of Protected Health Information (PHI)
<INSERT LOCAL HIPAA AUTHORIZATION LANGUAGE OR USE THE FOLLOWING>
As part of this research study, we are requesting your authorization or permission to review your 
child’s medical records to determine eligibility criteria for this study and any adverse events 
associated with testing. This information will be used for the purpose of determining the 
effectiveness and safety of the study drug(s) in individuals with hemophilia A.  This 
authorization is valid for an indefinite period of time.  We will obtain the following information: 
your child’s diagnosis, age, past medical history, diagnostic procedures, and results of any blood 


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tests, including results of genetic tests that were already done as part of your standard medical 
care.
As part of this research study, some information that we obtain from you will be placed into your 
child’s medical records held at <INSERT LOCAL SITE>, including the results of tests related to 
effectiveness, safety, and information related to any adverse events your child may suffer during 
these tests.
This identifiable medical record information will be made available to members of the research 
team for an indefinite period of time.
Your child’s medical information, as well as information obtained during this research study, 
may be shared with other groups, possibly including authorized officials from the study sponsor, 
federal regulatory agencies, and the University of Pittsburgh Office of Research Protections, for 
the purpose of monitoring the study.  Authorized representatives of <INSERT LOCAL SITE> or 
affiliated health care providers may also have access to this information to provide services and 
addressing billing and operational issues.
We will protect your privacy and the confidentiality of your child’s records, as described in this 
document, but cannot guarantee the confidentiality of your child’s research records, including 
information obtained from your child’s medical records, once your personal information is 
disclosed to others outside <INSERT LOCAL SITE>.
You can always withdraw your child’s authorization to allow the research team to review your 
medical records by contacting the investigator listed on the first page and making the request in 
writing.  If you do so, your child will no longer be permitted to participate in this study.  Any 
information obtained from your child up that point will continue to be used by the research team.
Is my or my child’s participation in this research study voluntary?
Your child’s participation in this research study, to include the use and disclosure of your child’s 
identifiable information for the purposes described above, is completely voluntary.  Whether or 
not you provide your consent for your child’s participation in this research study will have no 
effect on your child’s current or future relationship with the <INSERT LOCAL SITE>.  Whether 
or not you provide your consent for your child’s participation in this research study will have no 
effect on your child’s current or future medical care at <INSERT LOCAL SITE> or affiliated 
health care provider or your child’s current or future relationship with a health care insurance 
provider.
Your child’s doctor is involved as an investigator in this research study.  As both your doctor and 
a research investigator, s/he is interested both in your medical care and the conduct of this 
research study. Before your child agrees to participate in this research study, or at any time 
during your child’s study participation, you may discuss your child’s care with another doctor 
who is not associated with this research study. Your child is not under any obligation to 
participate in any research study offered by your child’s doctor.


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May I later withdraw my permission for my child to participate in this research study?
You may withdraw, at any time, your child’s consent for participation in this research study, to 
include the use and disclosure of your identifiable information for the purposes described above.  
Any identifiable research  or medical information recorded for, or resulting from, your child’s 
participation in this research study prior to the date that you formally withdrew your child’s 
consent may continue to be used and disclosed by the investigators for the purposes described 
above.
To formally withdraw your child’s consent for participation in this research study you should 
provide a written and dated notice of this decision to the principal investigator of this research 
study at the address listed on the first page of this form.
Your decision to withdraw your child’s consent for participation in this research study will have 
no effect on your current or future relationship with the <INSERT LOCAL SITE>.  Your 
decision to withdraw your child’s consent for participation in this research study will have no 
effect on your child’s current or future medical care at <INSERT LOCAL SITE> or affiliated 
health care provider or your or your child’s current or future relationship with a health care 
insurance provider.
If you withdraw, or the study doctor decides to discontinue, your child’s study drug treatment, 
your child may be asked to return for a follow-up visit.  If your child leaves this study, you will 
not lose any benefits to which you or he may be entitled.  
If my child agrees to take part in this research study, can he be removed from the study 
without our consent?
Your child may be withdrawn from this study by the study doctor or they may take your child 
out of the study if there is a reason. Some of the reasons the doctor may take your child out of the 
study include: your child’s condition worsens; the study is stopped; your child cannot meet all 
the requirements of the study; new information suggests taking part in the study may not be in 
your child’s best interests; you decide to take back your permission for us to collect, use or share 
your child’s health information. If you are unwilling to discontinue Emicizumab treatment prior 
to randomization, your child will no longer be eligible to participate in this study. You may also 
choose for your child to leave the study at any time. Your child’s participation in this study may 
be stopped by the study doctor at any time.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law. This Web site will not include information that can identify you. At most the Web 
site will include a summary of the results. You can search this Web site at any time.


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****************************************************************************** 
PARENTAL PERMISSION
 The above information has been explained to me and all of my current questions have been 
answered. I understand that I am encouraged to ask questions, voice concerns or complaints 
about any aspect of this research study during the course of this study, and that such future 
questions, concerns or complaints will be answered by a qualified individual or by the 
investigator(s) listed on the first page of this consent document at the telephone number(s) given. 
I understand that I may always request that my questions, concerns or complaints be addressed 
by a listed investigator. I understand that I may contact the Human Subjects Protection Advocate 
of the IRB Office, University of Pittsburgh (1-866-212-2668) to discuss problems, concerns, and 
questions; obtain information; offer input; or discuss situations in the event that the research 
team is unavailable. 
I understand that, as a child (age less than 18 years), the below-named child is not permitted to 
participate in this research study without my consent. Therefore, by signing this form, I give my 
consent for his participation in this research study and provide my authorization to share my 
child’s medical records with the research team. A copy of this consent form will be given to me.
__________________________________________ 
Printed Name of Child-Subject 
_________________________________________
____________________________
Parent’s or Guardian’s Name (Print) 
Relationship to Participant (Child)


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__________________________________________
__________________
Parent’s or Guardian’s Signature 
Date and Time
  
 
CERTIFICATION of INFORMED CONSENT 
I certify that I have explained the nature and purpose of this research study to the above-named 
individual(s), and I have discussed the potential benefits and possible risks of study participation. 
Any questions the individual(s) have about this study have been answered, and we will always be 
available to address future questions as they arise. I further certify that no research component of 
this protocol was begun until after this consent form was signed.
___________________________________ 
________________________ 
Printed Name of Person Obtaining Consent 
Role in Research Study 
_____________________________________
___________________
Name
Date and Time


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Table 1:  Schedule of Events
*Genotype, HLA are on buffy coat; **FVIII chromogenic is on aliquot of anti-FVIII; **ELISPOT is after 5 exposure days, in lieu of wk 
12 or 24, if closer.
Table 1
Schedule of Events
Study Week                        
Week 
0
Week 
4
Week
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
Screening, consent
X
Initiate study arms
X
Initiate study diary
X
Clinical monitoring
X
X
X
X
X
X
X
X
X
X
X
X
End-of-study visit
X
Laboratory tests
Anti-FVIII NBU chromogenic
X
X
X
X
X
X
Hemophilia genotype*
X
HLA type*
X
FVIII chromogenic (trough)*
X
X
X
X
X
X
T cell (ELISPOT,Ig, RNA)**
X
X
X**
X**
X
X
Microbiome
X
Sample for storage
X
X
X
X
X
X