Weight-based Dosing in Hemophilia A

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hemophilia

Intervention / Treatment
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* Drug: rFVIII


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males age 18 or older. Hemophilia A (FVIII activity 40% or less). Overweight or obesity defined as a BMI of 25.0-29.9 and ≥ 30 mg/m2, respectively. Exclusion Criteria: 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. Allergy to FVIII products. Current rFVIII requirements do not include at least a 72-hour period without rFVIII administration.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TBW, LBM, IBW<br>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). | Drug: rFVIII<br>* 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)].<br>* Other names: eloctate, advate, helixate, kogenate, recombinant;|
| Experimental: LBM, IBW, TBW<br>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). | Drug: rFVIII<br>* 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)].<br>* Other names: eloctate, advate, helixate, kogenate, recombinant;|
| Experimental: IBW, TBW, LBM<br>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). | Drug: rFVIII<br>* 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)].<br>* Other names: eloctate, advate, helixate, kogenate, recombinant;|
| Experimental: TBW, IBW, LBM<br>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). | Drug: rFVIII<br>* 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)].<br>* Other names: eloctate, advate, helixate, kogenate, recombinant;|
| Experimental: LBM, TBW, IBW<br>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). | Drug: rFVIII<br>* 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)].<br>* Other names: eloctate, advate, helixate, kogenate, recombinant;|
| Experimental: IBW, LBM, TBW<br>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). | Drug: rFVIII<br>* 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)].<br>* Other names: eloctate, advate, helixate, kogenate, recombinant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Dosed Based on LBM (Lean Body Mass) and TBW (Total Body Weight) Achieving Desired Peak FVIII Recovery. | Desired peak FVIII recovery value of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion based on LBM and TBW. 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. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Dosed Based on IBW (Ideal Body Weight) and TBW (Total Body Weight) Achieving Desired Peak FVIII Recovery. | Desired peak FVIII recovery value of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion based on IBW and TBW. 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. | 3 weeks | 
| Proportion of Subjects Dosed Based on LBM (Lean Body Mass) and IBW (Ideal Body Weight) Achieving Desired Peak FVIII Recovery. | Desired peak FVIII recovery value of 2 +/- 0.2 IU/dl per IU/kg (100 +/- 10%) at 10 minutes following infusion based on 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. | 3 weeks |