Conditions: Hemophilia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 30
Healthy volunteers: no

Brief summary:
Hemophilia A is an inherited (genetic) disease where a protein, factor VIII (FVIII), which promotes blood clotting is missing or does not work properly. Individuals with hemophilia A are at risk for bleeding. Bleeding is prevented and/or treated with recombinant factor VIII (rFVIII), which is an FDA-approved treatment for Hemophilia A. Obesity is common among patients with hemophilia. Some studies have shown that obese hemophilia patients may be able to prevent bleeding with a lower dose of clotting factor than the dose they are currently receiving. The lower dose is calculated based on what a patient should weigh rather than what he does weigh. This is a clinical research study to test whether calculating rFVIII dosing based on lean body mass and ideal body weight (what a person should weigh based on his height) in overweight and obese patients with hemophilia is more accurate than calculating rFVIII dosing based on what a person actually weighs.

Detailed description:
The investigators propose a single center, randomized, controlled, open-label, crossover trial to determine if recombinant factor VIII (rFVIII) dosed according to lean body mass (LBM) and ideal body weight (IBW) achieves a targeted FVIII recovery with better precision than based on total body weight (TBW). The investigators hypothesize the use of LBM and IBW to determine the dose of rFVIII necessary to attain a desired FVIII recovery of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) in overweight and obese (body mass index greater than or equal to 25 mg/m2), adult males (age 18 or older) with hemophilia A (FVIII activity 40% or less) will result in a 50% greater proportion of subjects within this range when compared to TBW. Eligible patients receiving care at the Hemophilia Center of Western Pennsylvania (HCWP) will be enrolled during clinic visits. Following enrollment and completion of screening assessment, subjects will present to HCWP for three study visits with each study visit occurring on successive weeks. Subjects will not have received any rFVIII for a period of at least 72 hours prior to each study visit. Recombinant FVIII infusion based on TBW, LBM, or IBW will take place during each study visit, and the order will be determined by randomization. During each study visit, FVIII levels will be assessed by obtaining blood samples before and at 10 and 30 minutes and 1 hour after infusion. Outcomes include the proportion of subjects achieving a desired peak FVIII recovery value of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion of rFVIII dosed according to LBM and TBW, IBW and TBW, and LBM and IBW. The investigators will use mixed effects logistic regression to investigate the effect of using different weight-based dosing methods on attaining target FVIII levels. We aim to have 24 subjects successfully complete the study.

Arms:
arm 1: Subjects will be randomized to receive rFVIII doses calculated by 3 separate methods over a 3 week period. Week 1, the dose will be based on TBW (Total Body Weight); Week 2, the dose will be based on LBM (Lean Body Mass); and Week 3, the dose will be based on IBW (Ideal Body Weight). arm 2: Subjects will be randomized to receive rFVIII doses calculated by 3 separate methods over a 3 week period. Week 1, the dose will be based on LBM (Lean Body Mass); Week 2, the dose will be based on IBW (Ideal Body Weight); and Week 3, the dose will be based on TBW (Total Body Weight). arm 3: Subjects will be randomized to receive rFVIII doses calculated by 3 separate methods over a 3 week period. Week 1, the dose will be based on IBW (Ideal Body Weight); Week 2, the dose will be based on TBW (Total Body Weight); and Week 3, the dose will be based on LBM (Lean Body Mass). arm 4: Subjects will be randomized to receive rFVIII doses calculated by 3 separate methods over a 3 week period. Week 1, the dose will be based on TBW (Total Body Weight); Week 2, the dose will be based on IBW (Ideal Body Weight); and Week 3, the dose will be based on LBM (Lean Body Mass). arm 5: Subjects will be randomized to receive rFVIII doses calculated by 3 separate methods over a 3 week period. Week 1, the dose will be based on LBM (Lean Body Mass); Week 2, the dose will be based on TBW (Total Body Weight); and Week 3, the dose will be based on IBW (Ideal Body Weight). arm 6: Subjects will be randomized to receive rFVIII doses calculated by 3 separate methods over a 3 week period. Week 1, the dose will be based on, IBW (Ideal Body Weight); Week 2, the dose will be based on LBM (Lean Body Mass); and Week 3, the dose will be based on TBW (Total Body Weight).

Interventions: intervention 1: rFVIII
Intervention descriptions: intervention 1: Recombinant FVIII concentrate is an FDA approved, and both efficacious and safe, therapy for the treatment and prevention of bleeding in hemophilia A. The rFVIII infusion dose will be calculated as follows: \[(weight in kg x desired FVIII increase of 100 IU/dL)/(2)\].

Protocol document:
Prot_SAP_000.pdf: 
Protocol Title:  
 
Weight-based Dosing in Hemophilia A: A randomized, controlled, open-label,  
 
 
 
 
crossover trial to measure factor VIII recovery following factor VIII concentrate  
 
 
 
 
dosing based on total body weight, ideal body weight, and lean body mass 
 
 
Principle Investigator: 
Craig D. Seaman, MD 
 
 
 
 
Assistant Professor of Medicine 
 
 
 
 
Department of Medicine 
 
 
 
 
Division of Hematology/Oncology    
 
 
 
 
University of Pittsburgh  
 
 
 
 
Associate Director, Hemophilia Center of Western Pennsylvania 
 
 
 
 
3636 Boulevard of the Allies        
 
 
 
 
 
 
Pittsburgh, PA 15213          
 
 
Co-Investigators: 
 
Margaret Ragni, MD, MPH          
  
 
 
 
 
Professor of Medicine        
 
 
 
 
Department of Medicine 
 
 
 
 
Division of Hematology/Oncology    
 
 
 
 
University of Pittsburgh 
 
  
 
 
 
 
Director, Hemophilia Center Of Western Pennsylvania               
 
 
 
  
 
 
3636 Boulevard Allies        
 
  
 
 
 
 
Pittsburgh, PA 15213          
 
 
 
 
 
 
 
Source of Support:  
University of Pittsburgh Cancer Institute 
 
 
NCT:  
 
 
02586012 
 
 
Date:  
 
 
5/6/19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
Abstract 
 
The increasing prevalence of obesity has not spared the hemophilia population with rates reflecting 
those of the general population. Obesity alters the pharmacokinetic properties of many drugs making it difficult 
to determine the dose to use when administering medications based on body weight. Under-or overdosing of 
clotting factor concentrates in hemophilia may result in catastrophic bleeding or heart attack and stroke, 
respectively. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight 
(IBW) are sometimes considered in these situations. It has been demonstrated that when recombinant factor 
VIII (rFVIII) is dosed according to total body weight (TBW) in overweight and obese hemophiliacs, FVIII 
recovery values are much greater than the expected 2 IU/dl per IU/kg. This value is only valid if the plasma 
volume is assumed to be 0.5 dL/kg; however, this assumption does not hold true in individuals whose weight 
and height differ markedly from the norm. These findings suggest the need for alternative methods of rFVIII 
dosing in individuals whose morphometric characteristics differ from the ideal and, further, suggest we are 
overdosing hemophilia A patients, which, considering the high price of rFVIII concentrates, is an economic 
issue contributing to rising healthcare costs.  
 
 
We propose a single center, randomized, controlled, open-label, crossover trial to determine if rFVIII 
dosed according to LBM and IBW achieves a targeted FVIII recovery with better precision than based on TBW. 
We hypothesize the use of LBM and IBW to determine the dose of rFVIII necessary to attain a desired FVIII 
recovery of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) in overweight and obese (body mass index greater than or 
equal to 25 mg/m2), adult males (age 18 or older) with hemophilia A (FVIII activity 40% or less) will result in a 
50% greater proportion of subjects within this range when compared to TBW. Eligible patients receiving care at 
the Hemophilia Center of Western Pennsylvania (HCWP) will be enrolled during clinic visits. Following 
enrollment and completion of screening assessment, subjects will present to HCWP for three study visits with 
each study visit occurring on successive weeks. Subjects will not have received any rFVIII for a period of at 
least 72 hours prior to each study visit. Recombinant FVIII infusion based on TBW, LBM, or IBW will take place 
during each study visit, and the order will be determined by randomization. During each study visit, FVIII levels 
will be assessed by obtaining blood samples before and at 10 and 30 minutes and 1 hour after infusion. 
Outcomes include the proportion of subjects achieving a desired peak FVIII recovery value of 2 +/- 0.2 IU/dl 
per IU/kg (100 +/- 10%) at 10 minutes following infusion of rFVIII dosed according to LBM and TBW, IBW and 
TBW, and LBM and IBW. We will use mixed effects logistic regression to investigate the effect of using 
different weight-based dosing methods on attaining target FVIII levels. In conclusion, if alternative weight-
based FVIII dosing achieves acceptable FVIII recovery, the findings would be noteworthy and practice-
changing, resulting in significant healthcare cost savings. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
1.0 Background 
1.1 Obesity and Hemophilia 
 
Obesity in the United States has reached epidemic proportions resulting in a major public health crisis. 
Current estimates reveal more than 35% of adults to be obese with the prevalence increasing steadily over the 
past few decades.1 Obesity is responsible for a number of health problems, including cardiovascular disease, 
hypertension, hyperlipidemia, type II diabetes mellitus, and osteoarthritis among many others.1 Medical costs 
related to obesity account for 10% of all medical spending and total approximately $147 billion per year.2 
Obesity is defined as a body mass index (BMI) greater than or equal to 30 mg/m2.1 BMI is calculated as 
follows: [(weight in kg)/(height in m2)].1 The increased frequency of obesity in hemophilia has been 
documented. The CDC found 23.5% of hemophilia patients 20 years of age or older in the United States were 
obese.3 Individuals with hemophilia are at risk for the same obesity related comorbidities as those in the 
general population, such as cardiovascular disease, hypertension, hyperlipidemia, etc.3 Additionally, obesity in 
hemophilia increases the risk of hemophilic joint disease, which leads to chronic arthritis, joint replacement 
surgeries, and lifelong disability.3 
 
1.2 Obesity and the Pharmacokinetics of Drug Therapy 
 
Obesity may significantly alter the pharmacokinetic properties of drugs, particularly volume of drug 
distribution and clearance, and is concerning, especially when administering weight-based medications with a 
narrow therapeutic index or high cost.4 Alternative descriptors of body weight have been used with a number of 
medications, including aminoglycosides, antineoplastic agents, and general anesthetics, in obesity.4 Two such 
methods are ideal body weight (IBW) and lean body mass (LBM). IBW is calculated in males as follows: [(50 
kg) + (2.3 kg x height in inches > 60)].5 LBM is calculated in males as follows: [(9.27 x 103 x TBW in kg)]/[(6.68 
x 103) + (216 x BMI)].6 It is not known if LBM or IBW, or some other descriptor of body weight, such as adjusted 
body weight, is more precise in determining drug dose when administering weight-based therapies.7 What is 
known is that while there is no single best descriptor for describing all of a drug’s pharmacokinetic properties in 
obesity, certain descriptors fare better than others in certain situations.7 Total body weight (TBW) appears to 
be more appropriate when describing volume of distribution, particularly important with moderate to highly 
lipophilic drugs, and LBM appears to be more accurate when describing clearance, significant in chronically-
dosed drugs.7 
 
1.3 Pharmacokinetics of FVIII concentrates 
 
Hemophilia A is an inherited X-linked recessive disease resulting from deficiency of clotting factor VIII 
(FVIII) which manifests as spontaneous and/or traumatic bleeding involving joints, muscles, mucocutaneous 
surfaces, and the central nervous system.8 The prevention and treatment of bleeding in hemophilia A is 
accomplished by the intravenous infusion of FVIII concentrates.8 Dosing is weight-based, and the calculation 
used to determine FVIII dosing is as follows: [(weight in kg x desired FVIII increase in IU/dL)/(2)] where 2 is the 
expected FVIII recovery value in IU/dL per IU/kg.9 Ingram first validated this formula in 1981 after Rizza 
observed in 1976 that the following calculation resulted in an expected FVIII recovery value of 2: [weight in kg x 
observed FVIII recovery in IU/dL)/(dose in IU)].10, 11 It is not known if FVIII dosing should continue to be based 
on TBW in overweight and obese individuals. Recent studies have shown that the observed FVIII recovery 
value is dependent on TBW with one study reporting median FVIII recovery values of 2.30 and 2.70 in patients 
with a BMI of 25-29 and 30 mg/m2 or higher, respectively, using current TBW-based dosing.9 Similarly, another 
study reported median FVIII recovery values of 2.18 and 2.68 in patients with a BMI of 25-29 and 30 mg/m2 or 
higher, respectively.12 These results differ from the expected FVIII recovery value of 2. Ingram cautioned this 
value was only valid if the patient’s plasma volume is assumed to be 0.5 dL/kg, with approximately 85% of 
FVIII confined to the intravascular space in the steady state.10, 13 This assumption, however, does not hold true 
in individuals whose weight and height differ markedly from the norm.9, 13 Plasma volume correlates well with 
lean body mass but does not vary proportionally with extremes in weight.14, 15 Adipose tissue, which accounts 
for the majority of increased TBW in obese individuals, is less vascular, therefore, contains less plasma 


volume, than lean body mass.14, 15 Moreover, 20-40% of the excess TBW in obesity is due to supporting tissue, 
e.g. muscle and connective tissue, which contains more plasma volume than adipose tissue alone.14, 15 Thus, 
obese patients are expected to have less plasma volume than their average weight counterparts.14, 15   
 
 
The above findings support alternative methods of FVIII dosing in individuals whose morphometric 
characteristics differ from the ideal, i.e. overweight and obese individuals, and suggest among this group, the 
dose given may exceed what is required, resulting in an unjustified higher cost, as compared with non-obese 
individuals.  
 
1.4 Preliminary Information 
 
We performed a retrospective pharmacokinetic analysis of hemophilia A patients administered 
recombinant FVIII (rFVIII) based on IBW, which showed peak levels and half-life comparable to standard 
dosing based on TBW (Table 1).16 One subject, with a BMI of 45.8, required an additional 25% of rFVIII to 
achieve an adequate peak FVIII level. It is hypothesized that LBM-based dosing would have been more 
accurate in this subject, and all morbidly obese patients because it accounts for weight due to supporting 
tissue rather than assuming excess weight is solely due to adipose tissue.  
 
Table 1.  Pharmacokinetic analysis of rFVIII utilizing IBW based dosing in hemophilia.  
 
BMI 
TBW based 
rFVIII dose 
IBW based 
rFVIII dose 
Peak FVIII level 
Patient 1 
45.8 
7550 
3800 
0.78 
Patient 2 
30.0 
4550 
3535 
0.97 
Patient 3 
33.8 
5000 
3350 
1.04 
Patient 4  
31.5 
5750 
4225 
1.23 
Patient 5 
35.1 
5900 
3900 
1.06 
Patient 6 
39.7 
6100 
3535 
0.97 
 
 
 
Given these results, along with the changes in plasma volume that occur in obesity, coupled with 
Ingram’s findings, and the fact that rFVIII is predominantly confined to the intravascular space, we hypothesize 
that LBM and IBW are better descriptors of body weight than TBW when determining rFVIII dosing in 
overweight and obese patients with hemophilia A.  
 
 
We, therefore, propose a single-center, randomized, controlled, open-label, crossover trial to determine 
if rFVIII dosing based on LBM and IBW achieves a targeted FVIII recovery, 2 +/- 0.2 IU/dl per IU/kg (100 +/- 
10%), with better precision than based on TBW in overweight and obese, adult males with hemophilia A (FVIII 
activity 40% or less). We hypothesize using LBM and IBW to determine the dose of rFVIII necessary to attain a 
desired FVIII recovery of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) in overweight and obese, adult males with 
hemophilia A will result in a 50% greater proportion of subjects within this range when compared to TBW. 
 
2.0 Significance 
 
The prevalence of obesity in the general population has increased significantly over the course of the 
past few decades with greater than 1/3 of the United States adult population considered obese.1 The obesity 
epidemic has not spared the hemophilia population with obesity affecting close to 25% of adults in the United 
States.3 Obesity may significantly alter the pharmacokinetic properties of drugs.4 FVIII concentrates are dosed 
according to TBW and calculated as follows: [(weight in kg x desired FVIII increase in IU/dL/(2)] where 2 is the 
expected FVIII recovery value in IU/dL per IU/kg and considered valid only when the plasma volume is 
assumed to be 0.5 dL/kg.9 However, plasma volume does not increase proportionally with TBW as a result of 
the decreased vascularity of adipose tissue, so plasma volume per kg of body weight in obesity is less than 
that observed in normal weight individuals.14, 15 Recent studies have shown that current FVIII concentrate 
dosing in overweight and obese individuals results in FVIII recovery values greater than desired suggesting 
that current dosing may exceed required levels for treatment of bleeds, surgery, or trauma in individuals with 
hemophilia A.9, 12  
 
 
If dosing exceeds requirement in hemophilia A, there are significant economic implications. The current 
standard of care for the treatment of hemophilia A in the United States is rFVIII, for which the average 


wholesale cost is $1 per unit infused, which for a 70 kg male on prophylaxis, is several hundred thousand units 
and several hundred thousand dollars annually.17 One United States center estimated a monthly cost savings 
of $120,000 if 20 overweight and/or obese pediatric patients receiving prophylactic therapy were dosed using 
IBW rather than TBW, which equates to an approximate $1.5 million cost savings annually.17 If alternative 
weight-based FVIII dosing achieves acceptable FVIII recovery, the findings would be noteworthy and practice-
changing, resulting in significant healthcare cost savings. 
 
3.0 Objectives 
3.1 Primary Objective 
To demonstrate that rFVIII dosed according to LBM achieves a targeted FVIII recovery, 2 +/- 0.2 IU/dl per 
IU/kg (100 +/- 10%), with better precision than based on TBW in overweight and obese (body mass index 
greater than or equal to 25 mg/m2), adult males (age 18 or older) with hemophilia A (FVIII activity 40% or less). 
 
Primary hypothesis: The use of LBM to determine the dose of rFVIII necessary to attain a desired FVIII 
recovery of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) in overweight and obese, adult males with hemophilia A will 
result in a 50% greater proportion of subjects within this range when compared to TBW. 
 
3.2 Secondary Objective 
To demonstrate dosing rFVIII based on IBW achieves a targeted FVIII recovery, 2 +/- 0.2 IU/dl per IU/kg (100 
+/- 10%), with better precision than based on TBW in overweight and obese (body mass index greater than or 
equal to 25 mg/m2), adult males (age 18 or older) with hemophilia A (FVIII activity 40% or less). 
 
Secondary hypothesis: Determining the rFVIII dose necessary to achieve a desired FVIII recovery of 2 +/- 0.2 
IU/dl per IU/kg (100 +/- 10%) in overweight and obese, adult males with hemophilia A utilizing IBW will result in 
a 50% greater proportion of subjects within this range when compared to TBW. 
 
4.0 Selection and Enrollment of Subjects 
4.1 Inclusion criteria  
The following criteria are required for study inclusion: 
 
1. Adult males age 18 or older. 
 
2. Hemophilia A (FVIII activity 40% or less). 
 
3. Overweight or obesity defined as a BMI of 25.0-29.9 and ≥ 30 mg/m2, respectively. 
 
4.2 Exclusion criteria  
Presence of any of the following criteria will result in study exclusion: 
 
 
1. Prior history of, or currently detectable, FVIII inhibitor defined as greater than or equal to 0.6 Bethesda Units 
(BU); however, a subject with a past low-level non-responding inhibitor defined as less than 5 BU, with no 
increase in titer following FVIII exposure, and not detectable within 12 months of the study, despite FVIII 
exposure during that period, will be allowed to enroll on study. 
 
2. Allergy to FVIII products 
 
3. Current rFVIII requirements do not include at least a 72-hour period without rFVIII administration 
 
4.3 Enrollment 
 
All subjects will be enrolled at the Hemophilia Center of Western Pennsylvania (HCWP). We aim to 
enroll 24 subjects over two years (12 per year). Potentially eligible patients will be approached to determine 
interest in study participation during clinic visits at HCWP. If a patient is interested in the study, he will discuss 
the study in further detail during the screening visit, which does not need to be a separate visit if the patient is 
already at HCWP for clinic visit or another reason. Discussion will include the purpose, protocol specifics as 
they relate to the patient, potential adverse effects, and risks and benefits of the study. Each potential subject 


will be encouraged to ask all questions that he feels are necessary to enable him to make an informed decision 
regarding participation in the study. Each potential subject will be encouraged to take the time needed for 
thoughtful consideration whether or not to participate in the study. Subjects who read the consent form are free 
to refuse enrollment. The principle investigator (PI) or co-investigator will obtain informed consent. No 
experimental interventions will occur until after informed consent is obtained. If any new information occurs 
during the conduct of the study, subjects who have been consented will be informed and will be re-consented 
with this information at the next study visit.  
 
 
The PI or a member of the research staff will conduct subject enrollment and screening. Subjects will 
be considered enrolled in the study after informed consent is obtained. Once enrolled, each subject will receive 
a unique subject identification number (i.e. PK001, PK002, etc.). No subject may begin the study prior to 
enrollment and assignment of a unique subject identification number. Screening assessment will be completed 
following enrollment. All individuals receiving a unique subject identification number will have any reason for 
study non-participation documented. Any subject identification numbers that are assigned will not be reused 
even if the subject does not receive treatment.  
 
 
Study participants will be free to withdraw at any time. All data collected prior to the time of withdrawal 
will be analyzed, but no additional information will be collected. Processed blood sample results will continue to 
be used; however, remaining samples will be destroyed or used as indicated by the subject. The reason and 
date of study withdrawal for all subjects will be recorded.  
 
5.0 Randomization 
 
Subjects will undergo randomization within 24 hours of enrollment and completion of screening 
assessment. Randomization is for the order of TBW, LBM, and IBW dosing for each subject. Permuted block 
randomization will be performed by the Center for Research on Healthcare Data Center (CRHC DC) web-
based data entry system. Subjects will be randomized to 1 of 6 possible dosing scenarios based on 3 different 
weight-dosing regimens being evaluated (TBW, LBM, and IBW) (Table 2).  
 
Table 2. Randomization Scenarios. 
 
1st Week  
(study visit 1) 
2nd Week 
(study visit 2) 
3rd Week 
(study visit 3) 
Scenario 1 
TBW 
LBM 
IBW 
Scenario 2 
LBM 
IBW  
TBW 
Scenario 3 
IBW 
TBW 
LBM 
Scenario 4 
TBW 
IBW 
LBM 
Scenario 5 
LBM 
TBW 
IBW 
Scenario 6 
IBW 
LBM 
TBW 
 
 
6.0 Study Intervention 
 
Recombinant FVIII concentrate is an FDA approved, and both efficacious and safe, therapy for the 
treatment and prevention of bleeding in hemophilia A. Given the preliminary data described above, standard of 
care at HCWP now includes pharmacokinetic testing to determine which weight-based dosing method 
achieves targeted FVIII recovery with the greatest precision in overweight and obese patients with hemophilia 
A; therefore, each subject will use his own rFVIII for the purposes of the study. Recombinant FVIII includes all 
recombinant FVIII brand products. Subjects will receive rFVIII during each of three study visits occurring on 
successive weeks and will not have received rFVIII for a period of at least 72 hours prior to each study visit 
(Table 3). Potential subjects whose current rFVIII requirements do not include at least a 72-hour period without 
rFVIII administration will not be eligible for study participation until rFVIII is being given in a routine, which 
includes a 72-hour period without rFVIII treatment. If at anytime during the study, rFVIII is necessary for non-
research purposes, the next study visit will be postponed until at least 72 hours following the last non-research 
related rFVIII treatment. Study participation will not limit the amount of rFVIII necessary for clinical purposes.  
 
 
Recombinant FVIII will be administered according to current FDA approved indications and dosing. The 
rFVIII infusion dose will be calculated as follows: [(weight in kg x desired FVIII increase of 100 IU/dL)/(2)]. TBW 
will be used to determine weight in kg, or it will be determined using LBM or IBW (see Appendix 1 for details 


regarding BMI, LBM, and IBW calculations). Subjects whose FVIII recovery is less than the desired 2 +/- 0.2 
IU/dl per IU/kg will not receive additional rFVIII as this is not done in routine clinical practice outside of active 
bleeding or bleeding prophylaxis prior to surgery. The HCWP nurse, per standard of care, will record details of 
the storage, lot number, stability, production, and expiration dates. A member of the research staff will ensure 
documentation of date, time, and amount of rFVIII infusion administered are recorded for data submission. 
 
7.0 Clinical and Laboratory Evaluations 
 
Eligible patients receiving care at HCWP will be enrolled during clinic visits. Following enrollment, 
completion of screening assessment and randomization, subjects will present to HCWP for three study visits 
with each study visit occurring on successive weeks (Table 3). Subjects will not have received any rFVIII for a 
period of at least 72 hours prior to each study visit. Recombinant FVIII infusion based on TBW, LBM, or IBW 
will take place during each study visit, and the order will be determined by randomization (Table 2). The HCWP 
nurse will perform rFVIII infusion over 5 to 10 minutes using a winged (butterfly) infusion needle. One-stage 
trough, peak, and recovery FVIII levels will be obtained on 0.5 ml citrate blood samples drawn before infusion 
and 10 minutes  (+/- 1 minute), 30 minutes (+/- 5 minutes), and 1 hour (+/- 5 minutes) after infusion. If at 
anytime during the study, rFVIII is necessary for non-research purposes, the next study visit will be postponed 
until at least 72 hours following the last non-research related rFVIII treatment. 
 
 
A member of the research staff will collect all data (Table 3). During the screening visit, FVIII inhibitor 
status will be assessed and based on routine comprehensive clinic anti-FVIII titer within the last 12 months. If 
no anti-FVIII titer has been performed during that time period, FVIII inhibitor status will be assessed during the 
screening visit using the Bethesda assay for which one 5 ml blood sample will be obtained when applicable. 
Also, documentation of an allergy to FVIII products will be obtained from the subject’s medical record. Subjects 
meeting exclusion criteria during screening visit will return for study visits 1, 2, and 3. During study visit 1, 
weight and height will be recorded followed by calculation of BMI, TBW, LBM, and IBW (see Appendix 1). 
During each study visit, one-stage trough, peak, and recovery FVIII levels will be obtained on 0.5 ml citrate 
blood samples drawn before and 10 minutes  (+/- 1 minute), 30 minutes (+/- 5 minutes), and 1 hour (+/- 5 
minutes) after infusion. All blood samples will be obtained by a research nurse with a maximum anticipated 
volume of 2 ml needed for each visit, which will be sent to the Institute for Transfusion Medicine Coagulation 
Laboratory in Pittsburgh, PA. During each study visit, adherence will be measured by the proportion of FVIII 
levels obtained (12 FVIII levels are needed – 4 per study week x 3 study weeks). 
 
Table 3. Study Calendar. 
 
Screening 
Visit 
TBW 
Week 
 
Study 
Visit 1 
LBM Week 
 
Study 
Visit 2 
IBW Week 
 
Study 
Visit 3 
FVIII inhibitor status assessed 
X 
 
 
 
Allergy to FVIII products recorded 
X 
 
 
 
Height and weight recorded  
 
X 
 
 
BMI, TBW, LBM, and IBW calculated 
 
X 
 
 
rFVIII infused according to TBW 
 
X 
 
 
rFVIII infused according to LBM 
 
 
X 
 
rFVIII infused according to IBW 
 
 
 
X 
FVIII level checked prior to rFVIII infusion  
 
X 
X 
X 
FVIII level checked 10 minutes (+/- 1-minute 
following rFVIII infusion 
 
X 
X 
X 
FVIII level checked 30 minutes (+/- 5 minutes) 
following rFVIII infusion 
 
X 
X 
X 
FVIII level checked 1 hour (+/- 5 minutes) 
following rFVIII infusion 
 
 
 
 
Adherence recorded 
 
X 
X 
X 
AEs recorded 
 
X 
X 
X 


 
8.0 Adverse Events 
 
All subjects enrolled in the study and having received any FVIII concentrate infusion will be included in 
the safety evaluation and all adverse events (AEs) will be recorded. Potential AEs include risk of blood 
drawing, including bleeding; allergic reaction; FVIII inhibitor development; and thrombosis.  
 
1. Blood drawing 
There may be discomfort, which is common, with drawing blood, which may include pain, lightheadedness, 
dizziness, syncope, ecchymosis, bleeding, or infection in the tissue surrounding the vein. Appropriate medical 
intervention may consist of applying pressure to resolve bleeding or antibiotics in the setting of infection. 
 
 
2. Allergic reaction 
Allergic reactions are rarely, if ever, reported with the use of rFVIII. Adverse events will be classified using the 
Common Terminology Criteria for Adverse Events (CTCAE) system, volume 4.03, 2010.18 Allergic type 
symptoms may include fever, chills, pruritis, rash, urticaria, paresthesias, chest pain, dyspnea, wheezing, 
nausea, vomiting, edema, tachycardia, hypotension, anaphylaxis, or death. Subjects will be monitored for the 
development of these symptoms. If these symptoms occur, and are felt to be the result of rFVIII, the infusion 
will be discontinued, and appropriate medical interventions will be administered. Anaphylaxis will result in study 
exclusion. The decision regarding study exclusion in less severe, or minor, allergic reactions will be at the 
discretion of the PI.  
 
3. FVIII inhibitor 
FVIII inhibitors develop in up to 25% of individuals with severe hemophilia A, usually occurring during the first 
20 exposures, in childhood, with the incidence decreasing substantially after 150 treatment days and rarely, if 
ever, occurs among highly exposed adults.19, 20 Thus, there is a rare possibility of FVIII inhibitor development. 
Subjects will be monitored closely and if FVIII inhibitor development is suspected, assessment will be 
performed with the Bethesda assay. If FVIII inhibitor development does occur, the subject will be excluded 
from further study participation and appropriate medical treatment will be provided. 
 
4. Thrombosis 
FVIII concentrates are rarely, if ever, associated with the development of thrombotic complications. Subjects 
will be monitored closely and if thrombosis is suspected, the appropriate clinical evaluation will be performed. If 
thrombosis does occur, the subject will be excluded from further study participation, and appropriate medical 
treatment will be provided. 
 
5. Bleeding 
Because study subjects have hemophilia, there is a risk of bleeding. In the event that bleeding occurs at the 
infusion site, and cannot be stopped with pressure, it may be necessary to use an adhesive material to stop 
the bleeding. It is also possible that changing rFVIII schedule could cause bleeding. Additional rFVIII will be 
administered if this occurs. If bleeding is major, defined as a decrease in hemoglobin 2 grams per deciliter or 
more; transfusion of 2 or more units of red blood cells; or bleeding in a critical organ, such as intracranial, 
intraspinal, intraocular, pericardial, or retroperitoneal, the subject will be excluded from further study 
participation. If bleeding is minor, defined as all bleeding episodes that do not meet criteria for major bleeding, 
further study participation will be at the discretion of the PI.  
6. Inadvertent Disclosure 
There is a potential for disclosure or breach of confidentiality of collected data. In order to reduce these risks, 
research-related documents and clinical information stored in research files will be assigned an alphanumeric 
identifier. A linkage key for linking the assigned alphanumeric identifier with the subject’s name will be stored in 
locked files at HCWP. 
 
7. Potential benefits 
Study participation may not result in any direct clinical benefit; however, it may provide data supporting the 
efficacy of rFVIII dosed according to LBM and/or IBW for the prevention and treatment of bleeding in 
overweight and obese hemophiliacs, which will lead to significant healthcare-related cost savings.    


 
9.0 Statistical Considerations 
9.1 Outcomes 
9.1.1 Primary Outcome: The proportion of subjects achieving a desired peak FVIII recovery value of 2 +/- 0.2 
IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion of rFVIII dosed according to LBM and TBW.  
 
9.1.2 Secondary Outcome: The proportion of subjects achieving a desired peak FVIII recovery value of 2 +/- 
0.2 IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion of rFVIII dosed according to IBW and TBW.   
 
9.1.3 Secondary Outcome: The proportion of subjects achieving a desired peak FVIII recovery value of 2 +/- 
0.2 IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion of rFVIII dosed according to LBM and IBW.   
 
 
The proportions above will be determined by dividing the number of subjects attaining the desired peak 
FVIII recovery value by the total number of subjects. This will be done for TBW, LBM, and IBW. FVIII recovery 
values will be calculated as follows: [(weight in kg x observed FVIII recovery in IU/dL)/(dose in IU)] and 
expressed as IU/dL per IU/kg.  
 
9.2 Statistical Analysis 
 
Preliminary analyses will focus on data checks for completeness and accuracy and address any issues 
with data quality. Descriptive summaries will be examined including the mean and standard deviations (or 
medians and quartiles for skewed distributions) for continuous variables and frequencies and proportions for 
categorical variables. Since the crossover design involves 6 sequence groups with 3 intervention groups and 3 
periods, distributions of baseline characteristics and peak FVIII recovery value will be compared between the 
sequence groups to assess effectiveness of the randomization. Peak FVIII recovery value and the proportion 
achieving the target levels will be summarized by intervention group and by period. The primary outcome, 
attaining a peak FVIII recovery value of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) is binary. We will use mixed 
effects logistic regression to investigate the effect of using different weight-based dosing methods on attaining 
target FVIII levels. By having a random subject effect, this model would account for non-independence of 
observations due to the crossover design. In addition, it validly handles ignorable missing data, although 
dropout is expected to be minimal given the short duration of the study. Independent variables would include 
fixed intervention group effect and fixed period effect. Though we do not expect them to be significant, 
treatment by period interaction and carry-over effects would be included and tested for in the initial model. If 
these terms are significant, then adjusted intervention group effects will be reported. Appropriate linear 
contrasts will be constructed to compare TBW and LBM (Aim 1) and TBW and IBW (Aim 2) if the overall test 
for the intervention effect was found to be significant. Residual analyses will be conducted to identify sources 
of model misspecification, outliers, and possibly influential observations. As an exploratory aim, we will also 
determine if differences exist between LBM and IBW. Confidence intervals will be constructed and used for 
inference. All primary analyses for intervention group comparisons will use an intention-to-treat approach 
whereby all patients randomized are included in the analysis. All tests will be conducted at the 5% level.  
 
 
We base our sample size justifications on computational techniques that match our study design and 
proposed analytical approach as much as possible within the constraints of already published methodologies 
(PASS 13. NCSS, LLC. Kaysville, Utah). Accounting for an estimated lost to follow-up of 5%, the effective 
sample size is 22.8 total or 3.8 patients per sequence group. Using an alpha level of 5% and a two-sided 
McNemar test to compare LBM and TBW (or IBW and TBW), a sample size of 3 patients per sequence group 
would provide at least 80% power to detect difference in proportion of 0.50 assuming that that the proportion of 
discordant pairs is 0.6. A risk difference of 0.50 is a conservative estimate based on prior studies.3, 4 Since our 
actual analytical approach (mixed effects logistic model) is more precise, we will have higher power to detect 
this effect or the same power to detect a smaller effect. We propose to recruit a total of n=30 subjects (15 per 
year for two years) allowing for 3 screening failures per year. 
 
10.0 Data Collection, Site Monitoring, and Adverse Event Reporting 
10.1 Data Collection 
 
The PI or co-investigator will obtain informed consent. The PI will maintain all study data. All data 
required by the study protocol will be captured and managed by electronic Case Report Forms (CRFs) via 


web-based electronic data capture by the CHCR DC. All information will be stored on their server. Information 
will be stored in a secure database. No personal identifiers will be associated with the data. The University of 
Pittsburgh Research Conduct and Compliance Office may inspect records at any time. 
 
 
Data collection will cease at the time of withdrawal from the study; however, data collected up to the 
point of withdrawal will continue to be used. Following the required data retention period, data will be stored for 
an indefinite period of time on the CRHC DC secure server in its de-identified state. Following completion of 
the study, linkage codes will be destroyed. Any paper documents will be secured in long-term retention for an 
indefinite period of time. 
 
10.2 Data Safety Monitoring Plan (DSMP) 
 
The Data Safety Monitoring Committee (DSMC) will meet regularly to review all aspects of the study. 
The DSMC is comprised of the research team at HCWP consisting of study investigators, research nurses, and 
regulatory coordinator. Subjects will be closely monitored to ensure subject safety and to that procedures are 
in place to maintain privacy and confidentiality, progress of the 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 IRB 
according to regulations outlined in the IRB Reference Manual for the Use of Human Subjects. The DSMC will 
determine if the risk benefit ratio is sufficiently favorable that it is appropriate to continue the trial. The events 
are: 
 
• 
A subject experiences FVIII inhibitor development (defined as greater than or equal to 0.6 BU at ITxM) 
in association with rFVIII. 
• 
A subject experiences a thrombotic event in association with rFVIII.  
• 
A subject develops severe or catastrophic bleeding.  
• 
A subject develops a Grade 2 or greater allergic reaction in association with rFVIII, defined as follows 
using the CTCAE grading. 
o Grade 2 - Intervention or interruption of infusion necessary. Responds promptly to symptomatic 
treatment. Prophylactic medications indicated for less than or equal to 24 hours. 
o Grade 3 - Prolonged, or not rapidly responsive to symptomatic treatment and/or interruption of 
infusion. Recurrence of symptoms following initial improvement.  
o Grade 4 - Life-threatening consequences. Urgent intervention indicated. 
• 
A subject develops anaphylaxis in association with rFVIII, defined as follows using the CTCAE grading 
(all anaphylactic events are Grade 3 or higher). 
o Grade 3 - Symptomatic bronchospasm with or without urticaria. Allergy-related edema and/or 
angioedema. Hypotension. Parenteral intervention needed. 
o Grade 4 - Life-threatening consequences. Urgent intervention indicated. 
 
 
 
Such events will be handled as serious adverse events (SAEs) and reported in an expedited time frame 
to the IRB. The data concerning the event will be reviewed by the DSMC along with all other available data to 
determine appropriate follow-up, with a decision to continue enrollment and treatment of subjects at that time. 
Additionally, the following may also stop further subject enrollment and treatment.   
• 
The DSMC 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 DSMC. 
 
 
 
A report summarizing the above DSMP activities will be submitted to the IRB at the time of annual 
renewal. 
 
10.3 Adverse Event Reporting 
 
All AEs experienced by study subjects are to be recorded on the CRF, regardless of the severity of the event 
or its relationship to study treatment. The AE reporting procedures are based on the CTCAE system, volume 
4.03, 2010. Subjects will report any symptoms to the PI or research staff. The PI will determine if symptoms 
qualify as an AE or SAE with confirmation by one of the co-investigators. AEs 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 
AEs: 
 
• 
Not related: The event can readily be explained by factors not involving rFVIII, and a temporal 
relationship with rFVIII does not exist. 
• 
Possibly related: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of rFVIII 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 of rFVIII 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 the administration of rFVIII, follows a 
known or suspected response pattern to rFVIII, is confirmed by improvement upon stopping rFVIII, and 
reappears upon repeated exposure to rFVIII. 
 
 
The PI will follow up all AEs, regardless of severity, 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 PI. All SAEs will be reported to the IRB according to its guidelines. 
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 but does not necessarily have a causal relationship with the pharmaceutical product.  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.21 A 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. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity. 
• 
Results in a congenital anomaly/birth defect. 
 
 
A SAE may also be any other medically important event that, in the opinion of the PI, may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the definition above.  
 
11.0 Human Subjects 
11.1 Minority Inclusion and Non-Discriminatory Statements 
 
Overweight or obese (BMI greater than 25.0-29.9 and 30 mg/m2, respectively), adult males (age 18 or 
older) with hemophilia A (FVIII activity 40% or less) will be eligible for study participation. Children will not be 
enrolled in the study. As hemophilia A is an X linked recessive genetic disorder, greater than 98% of affected 
individuals are male, and approximately 90% are Caucasian; therefore, it is anticipated that the majority of 
subjects will be Caucasian males. There will be no discrimination based on gender, race, or ethnicity. The 
gender, racial, and ethnic characteristics of the proposed study population will reflect the demographics of the 
disease, the city of Pittsburgh and surrounding areas, and the University of Pittsburgh Medical Center (UPMC).  
 
11.2 Confidentiality  
 
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. In order to reduce risks of disclosure or 
breach of confidentiality, research related documents, blood samples, and clinical information stored in the 
subject’s research file will be assigned an alphanumeric identifier, i.e. BW001, which does not contain any 


personal identifying information. A linkage key for linking the assigned alphanumeric identifier with the subject’s 
name will be stored in locked files at HCWP. Any publication arising from this study will not contain names or 
other identifying information. 
 
11.3 Costs and Payments  
 
Subjects will not incur any costs related to study visits, rFVIII infusion, or laboratory testing. The 
research study is not paying for rFVIII. Each subject will use his own rFVIII for the purposes of the study. 
Research related costs are outlined in the budget proposal. Subjects will receive compensation up to $300.00 
($100.00 following each study visit completed). 
 
12.0 References 
1. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of obesity in the United States, 2009-2010. NCHS data 
brief, no. 82. Hyattsville, MD: National Center for Health Statistics. 2012. 
2. Finkelstein EA, Trogdon JG, Cohen JW, et al. Annual Medical Spending Attributable To Obesity: Payer-
And Service-Specific Estimates.  Health Affairs. 2009; 28(5):w822-w831. 
3. Wong TE, Majumdar S, Adams E, et al. Overweight and Obesity in Hemophilia A Systematic Review of 
the Literature. Am J Prev Med. 2011; 41(6S4):S369-S375. 
4. Cheymol G. Effects of Obesity on Pharmacokinetics Implications for Drug Therapy. Clin 
Pharmacokinet. 2000; 39(3): 215-231. 
5. Pai MP. Drug Dosing Based on Weight and Body Surface Area: Mathematical Assumptions and 
Limitations in Obese Adults. Pharmacotherapy. 2012; 32(9):856-868. 
6. Janmahasatian S, Duffull SB, Ash S, et al. Quantification of Lean Bodyweight. Clin Pharmacokinet. 
2005; 44(10):1051-1065. 
7. Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? 
British Journal of Clinical Pharmacology. 2004; 58(2);119-133. 
8. Tuinenburg A, Biere-Rafi S, Peters M, et al. Obesity in haemophilia patients: effect on bleeding 
frequency, clotting factor concentrate usage, and haemostatic and fibrinolytic parameters. Haemophilia. 
2013; 19:744-752. 
9. Henrard S, Speybroeck N, Hermans C. Body weight and fat mass index as strong predictors of factor 
VIII in vivo recovery in adults with hemophilia A. Journal of Thrombosis and Haemostasis. 2011; 
9:1784-1790. 
10. Ingram GI. Calculating the dose of factor VIII in the management of haemophilia. Br J Haematol. 1981; 
48:351–4. 
11. Rizza CR. The management of patients with coagulation factor deﬁciencies. In: Biggs R, ed. Human 
Blood Coagulation, Haemostasis and Thrombosis. Oxford: Blackwell Scientiﬁc Publications. 1976:374–
5. 
12. Henrard S, Speybroeck N, Hermans C. Impact of being underweight or overweight on factor VIII dosing 
in hemophilia A patients. Haematologica. 2013; 98(9):1481-1486. 
13. Björkman S, and Berntorp E. Pharmacokinetics of Coagulation Factors Clinical Relevance for Patients 
with Haemophilia. Clin Pharmacokinet. 2001; 40(11):815-832. 
14. Komwilaisak P and Blanchette V. Pharmacokinetic studies of coagulation factors: relevance of plasma 
and extracellular volume and body weight. Haemophilia. 2006; 12 (Suppl. 4):33-39. 
15. Feldschuh J and Enson Y. Prediction of the normal blood volume. Relation of blood volume to body 
habitus. Circulation. 1977; 56:605-612. 
16. Graham A and Jaworski K. Pharmacokinetic analysis of anti-hemophilic factor in the obese patient. 
Hemophilia. 2014;20:226-229. 
17. Johnson KA and Zhou Z. Costs of Care in Hemophilia and Possible Implications of Health Care 
Reform. Hematology Am Soc Hematol Educ Program. 2011:413-418. 
18. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 
June 14 2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
19. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. 
Haemophilia. 2013;19:e1-e47. 
20. Kempton CL, White GC. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood. 
2009;113:11-17. 
21. Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others 


and Adverse Events, September 3, 2013. Available at: 
 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2. 
 
13.0 Appendices 
13.1 Weight Calculations 
1. BMI in kg/m2 calculated as [(weight in kg)/(height in m2)] 
2. LBM in kg calculated as [(9.27 x 103 x TBW in kg)]/[(6.68 x 103) + (216 x BMI)] 
3. IBW in kg calculated as [(50 kg) + (2.3 kg x height in inches > 60)] 
4. TBW dose calculated as [(TBW in kg x desired FVIII level of 100 IU/dL)/(2)] 
5. LBM dose calculated as [(LBM in kg x desired FVIII level of 100 IU/dL)/(2)] 
6. IBW dose calculated as [(IBW in kg x desired FVIII level of 100 IU/dL)/(2)] 
 
13.2 Qualifications of Investigators 
 
Dr. Craig Seaman is an Assistant Professor of Medicine in the Department of Medicine, Division of 
Hematology and Oncology, at UPMC. His research focuses on hemostasis and thrombosis. He is currently 
completing his Master of Science degree in Clinical Research at the University of Pittsburgh Institute for 
Clinical Research Education. He is developing clinical research protocols with the support of his senior 
research mentor, Dr. Margaret Ragni. 
 
 
 
Dr. Margaret Ragni is a Professor of Medicine and the Director of HCWP, and has conducted numerous 
clinical research studies at the University of Pittsburgh, investigator-initiated and in collaboration with the CDC, FDA, 
NIH, and pharmaceutical agencies. She is an expert in the area of hemophilia treatment and complications, including 
AIDS and hepatitis, and management of joint hemorrhages.