Comparison of Ideal vs. Actual Weight Base Factor Dosing
Phase: NA
Conditions: Hemophilia A
Sponsor: Bloodworks

 
 
 
Comparison of Ideal vs. Actual Weight Base Factor Dosing 
Version 2.0 
 
October 12, 2016 

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Protocol: Weight based dosing version 2 – 12OCT2016 
Comparison of Ideal vs. Actual Weight Base Factor Dosing 
 
Background 
 
Hemophilia is an x-linked (mainly affecting males) genetic disorder characterized by 
a mutation in the clotting factor VIII gene (hemophilia A) or the clotting factor IX 
gene (hemophilia B) resulting in spontaneous and trauma-induced bleeding. This 
bleeding can be treated and prevented with clotting factor concentrate which has 
been available since the 1960s. A randomized clinical trial published in 2007 
[Manco-Johnson, NJEM 2007] established that prophylactic treatment with factor 
several times a week prevents bleeding and adverse clinical outcomes due to 
bleeding such as joint arthopathy. Thus, prophylactic treatment with clotting factor 
became standard of care.  
 
Clotting factor replacement is given intravenously and is based on a patient’s 
weight. The clotting factor circulates in the plasma with a half-life of hours to days 
(depending on the product). It does not get distributed in the adipose (fat) tissue. 
Although total plasma volume might increase with body mass index, it does not 
increase proportionally. The current standard of calculating a patient’s dose on 
actual body weight may overestimate the appropriate dose, and calculations based 
on ideal body weight may be more accurate.  Inappropriate dosing may not only be 
harmful for the patient but also leads to unnecessary health care cost.  
 
Hypothesis:  Factor dosing based on ideal body weight will result in hemostatic 
factor levels (recovery of at least 66% of predicted). 
Null Hypothesis: Factor dosing based on ideal body weight will not result in 
hemostatic factor levels (recovery of at least 66% of predicted). 
 
Trial Design 
 
This is a randomized, prospective, multicenter, open-label, cross-over study 
comparing the pharmacokinetics (PK) of ideal vs. actual body weight dosing of 
factor concentrate in overweight and obese participants with hemophilia A.  
 
The study will be conducted at the Washington Center for Bleeding Disorders 
(WCBD), Oregon Health & Science University (OHSU), Seattle Children’s Hospital 
(SCH) and Providence Sacred Heart Children’s Hospital (SH). Ethics approval will be 
obtained at each individual location before trial enrollment begins for that location. 
 
Primary outcomes: 
1. To compare the recovery to a 50 units/kg (±20%) dose of factor VIII (FVIII) 
concentrate in participants age 12 and above with hemophilia A when 
calculated on actual body weight (ABW) versus ideal body weight (IBW). 
2. To determine the likelihood of under dosing when using IBW or over-dosing 
with ABW 

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Protocol: Weight based dosing version 2 – 12OCT2016 
 
Secondary outcomes:  
- 
To determine the effect on half-life of these dosing strategies 
- 
To determine the effect on PK differences of hemophilia severity  
- 
To determine differences in participants receiving half-life (HL) vs. extended 
half-life (EHL) products 
- 
To determine the differences, if any, between overweight and obese 
participants 
 
Inclusion Criteria 
- 
At least 12 years of age  
- 
Hemophilia A  
- 
Male gender 
- 
Able and willing to comply with PK testing schedule 
- 
Either overweight or obese BMI (using CDC definitions by age) 
Table 1: The standard weight status categories associated with BMI ranges for adults (≥ 20 year old) 
BMI 
Weight Status 
Below 18.5 
Underweight 
18.5 – 24.9 
Normal or Healthy Weight 
25.0 – 29.9 
Overweight 
30.0 and Above 
Obese 
 
 
 

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Protocol: Weight based dosing version 2 – 12OCT2016 
Figure 1: The standard weight status categories associated with BMI ranges for boys (2 to 19 years)
 
Exclusion Criteria 
- 
Inhibitor of > 0.6 BU twice in the past, or documented abnormal recovery 
of less than 66% (of expected) in the past. 
- 
Known other bleeding disorder 
- 
Known other prolongation in aPTT (lupus anticoagulant, FXII deficiency) 
- 
Female gender 
 
Recruitment 
Participants will be recruited through the participating centers. Washington Center 
for Bleeding Disorders (WCBD), Oregon Health & Science University (OHSU), Seattle 
Children’s Hospital (SCH) and Providence Sacred Heart Children’s Hospital (SH). 
Cumulatively, up to 20 patients will be enrolled at all 4 sites . 
 
Randomization 
Randomization will be performed centrally at the Washington Center for Bleeding 
Disorders.  When a participant has completed the consent and eligibility forms and 
is able to be enrolled, the participating center will contact WCBD to receive the 
subject ID and treatment arm assignment.  Randomization will be determined by 

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Protocol: Weight based dosing version 2 – 12OCT2016 
blocked randomization. Subjects will be randomized to either undergo PK 
measurements based on actual body weight followed by ideal body weight OR PK 
measurements based on ideal body weight followed by actual body weight.  
 
Study design - Primary outcome: 
Participants age 12 and up and considered to be overweight or obese by either 
calculated BMI (ages 20 and over) or the McLaren method (ages 12 to 19) and 
diagnosed with hemophilia A of any severity will be enrolled. 
 
There must be a period of at least 48 hours for standard half-life products or at least 
72 hours for extended half-life products since the last dose of factor.  Participants 
will be randomized to receive 50 U/kg (±20%)  of the factor product they routinely 
use either based on IBW or ABW and will have pharmacokinetic (PK) labs drawn as 
described in the PK protocol section. After a period of at least 48 hours for standard 
half-life products or at least 72 hours for extended half-life products but no more 
than 60 days, participant will receive a second dose of factor at 50 U/kg (±20%) 
based on the alternate dosing strategy and will have a second set of PK labs drawn.   
 
Patients may bring and infuse their own factor, have it infused by their parents or by 
the clinic staff. Should there be bleeding during the study, the bleed should be 
treated as per the patient’s usual protocol.  
 
PK studies will be delayed until the resolution of any acute bleeding episodes [after 
a period of at least 48 hours for standard half-life products or at least 72 hours for 
extended half-life products].  If the participant has an acute bleed after the recovery 
draw, then that episode will not be used in the analysis.  The episode will be 
attempted again at a later date within the 2-month window. 
 
Intention to treat: 
If a participant experiences a 10% or greater change in BMI between the first and 
second dose, the participant will be included in the analysis. 
 
 
Minimum of 8 participants ages 12 and over
 
Minimum of 8 participants ages 12 and over 
 
 
Ideal body weight and BMI calculations: 
 
BMI Calculations: 
Sites shall use CDC website  to calculate BMI for all participants and to determine if 
participants are overweight or obese. 
dose on IBW
dose on actual BW
dose on actual BW
dose on IBW

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Protocol: Weight based dosing version 2 – 12OCT2016 
 
Ages 12 to <20: https://nccd.cdc.gov/dnpabmi/Calculator.aspx  
 
Ages 20 and older: 
http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/metric_bmi_calculat
or/bmi_calculator.html 
 
IBW Calculations: 
 
Ages 12 to <20: Sites shall use the McLaren method to calculate ideal body weight 
in participants under 20 years old. [Phillips et al 2007] 
http://www.cdc.gov/growthcharts/data/set1clinical/cj41c021.pdf 
 
 
 
Ages 20 and older: Sites shall use the following equation to calculate IBW in 
participants 20 years and older:  IBW = 50 kg + (2.3 kg * every inch over 5 feet) 
 
PK Protocol: 
 
PK studies will be measured in response to one 50 U/kg (±20%) dose of the 
participant’s current product.  Every effort shall be made to ensure the same size 

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Protocol: Weight based dosing version 2 – 12OCT2016 
vials and same lot numbers are used with the second dose to ensure the second dose 
is as similar to the first dose as possible. All participants will undergo PK testing 
twice: One test will be with 50 U/kg (±20%) for hemophilia A based on ideal body 
weight and the other test will be with 50 U/kg (±20%) for hemophilia A based on 
actual body weight.  
 
Post dose blood draws cannot be pulled from the port/IV that was used to 
administer factor. Sites may infuse factor through a peripheral line and obtain post 
blood draws through a port.  
 
Blood Draw Policy and Schedules: The baseline and the recovery draws for the first 
and second doses must be completed by the same laboratory (baseline laboratory). 
Baseline and peak (recovery) levels will be drawn in duplicate. The Duplicate draw 
will be spun and frozen for batch shipping/testing at the designated “reference” lab. 
Duplicate samples from OHSU and Seattle Children’s will be tested at WCBD, 
Duplicate samples from WCBD and Scared Heart will be tested at OHSU.  
 
Blood draws to measure half-life are encouraged to be drawn in the baseline 
laboratory, but may be drawn in other local laboratories and shipped to the baseline 
laboratory for analysis.  If the 30-minute recovery draw is missed participant can 
still be included with another attempt of the dose/PK draw if the second dose/draw 
falls within the 2 month window. 
 
Hemophilia A – regular half-life product  
Baseline – 30 ± 10 minutes – 5 to 7 hours – 20 to 26 hours – 44 to 50 
hours 
Hemophilia A – extended half-life factor 
Baseline – 30 ± 10 minutes – 5 to 7 hours – 20 to 26 hours – 44 to 50 
hours – 69 to 75 hours – 93 to 99 hours 
  
Statistics: 
 
The first primary endpoint will be assessed by evaluation of the mean paired 
difference in recovery between the two methods (IBW vs. ABW dosing) by paired t-
test or by Wilcoxon signed-rank test if recoveries are skewed. 
 
The second primary endpoint will be evaluated by extension of estimated recovery 
distribution to estimate the likelihood of failure (under-dosing or over-dosing) of 
each dosing strategy.  
 
For the first of the above evaluation measures, assuming approximate normality of 
recoveries, we estimate having 80% power to detect a mean reduction of 1 standard 
deviation in a study of 16 subjects assuming an intra-class correlation of at least 0.2.  
Greater (lesser) intra-class correlation would increase (decrease) statistical power 
for this evaluation.   
 

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Protocol: Weight based dosing version 2 – 12OCT2016 
In the event that the study is underpowered (due to a lower than anticipated intra-
class correlation), distributional summaries for each approach and for paired 
differences (including histograms) as well as for the intra-class correlation would be 
useful for design of future studies if the ideal weight base factor dosing is not 
deemed unacceptable  
 
Collecting and Reporting Adverse Events: 
 
Serious adverse events are defined as when the patient outcome is either death, life-
threatening, hospitalization (initial or prolonged), disability or permanent damage, 
congenital anomaly/birth defect, required intervention to prevent permanent 
impairment or damage, or other serious, important medical events.  Serious adverse 
events should be tracked per patient and reported centrally to the Washington 
Center for Bleeding Disorders.  Adverse events that do not meet the criteria for 
serious adverse events but qualify as Grade 3 or 4 adverse events will be recorded 
and reported.  
 
Information to collect and report on adverse events includes patient details, 
suspected medicinal product, other treatments, details of suspected adverse 
reactions, details on the reporter of the event. 
 
Funding: This research is funded by the Healthcare Authorities of Washington 
 
References 
 
1. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, 
Ingram JD, Manco-Johnson ML, Funk S, Jacobson 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 Aug 
9;357(6):535-44. 
 
2. Phillips S, Edlbeck A, Kirby M, Goday P. Ideal body weight in children. Nutr Clin 
Pract. 2007 Apr;22(2):240-5.