Minimize Menorrhagia in Women With Von Willebrand Disease

This is an outpatient, 24-week Phase III prospective, randomized, crossover trial comparing recombinant von Willebrand factor (rVWF) and tranexamic acid (TA, Lysteda®) to minimize menorrhagia in women with von Willebrand disease (VWD). The purpose of this Phase III multicenter prospective, randomized, crossover arm trial is to compare recombinant von Willebrand factor (rVWF) to tranexamic acid (TA) in reducing the severity of menorrhagia in women with von Willebrand disease.

In this study, women age 13-45 years with mild to moderate VWD and menorrhagia will be enrolled at their hemophilia treatment centers (HTCs) and provide information on menstrual bleeding from their two past monthly cycles to establish baseline bleeding frequency. Only women with regular menses, defined as menses every 21-35 days will be enrolled. A total of 60 subjects will be recruited and enrolled at approximately 25 HTC sites. Following enrollment, subjects will be randomized to Group I or Group II for the first five days of the next four consecutive menstrual cycles. Those randomized to Group I will be treated with Arm A for menstrual bleeding in cycles 1 and 2, followed by Arm B for menstrual bleeding in cycles 3 and 4. Those randomized to Group II will be treated with Arm B for menstrual bleeding in cycles 1 and 2, followed by Arm A for menstrual bleeding in cycles 3 and 4.

Subjects randomized to Group I will receive Arm A rVWF 40 IU/kg intravenously (IV) infusion on day 1 of each of two menstrual cycles, Cycles 1 and 2. They will then be crossed over to Arm B, TA 650 mg 2 tablets orally (po) three times daily on days 1-5 of each of two menstrual cycles, Cycles 3 and 4. Subjects randomized to Group II will receive Arm B, TA 650 mg 2 tablets orally (po) three times daily on days 1-5, for each of two menstrual cycles, Cycles 1 and 2. They will then be crossed over to Arm A, rVWF 40 IU/kg intravenously (IV) infusion on day 1 on each of two menstrual cycles, Cycles 3 and 4. This regimen may be given at the HTC clinic or at home by visiting nurse. Baseline laboratory studies will be drawn at screening, including Blood Counts: hemoglobin, white count, differential, platelets; Iron Tests: iron, total iron binding capacity (TIBC), ferritin; Thyroid Test: thyroid stimulating hormone (TSH); and Von Willebrand Tests (VWF and related tests). Before initiating treatment, subjects will be trained by the HTC nurse on 1) reading urine pregnancy tests and 2) completion of the pictorial blood assessment chart (PBAC), cycle severity score (CSR), and cycle length (CL); and 3) completion of patient diary. Following randomization, subjects will administer home pregnancy tests prior to the first of each 5-day dosing cycle. On each of the four dosing cycles, Cycles 1-4, the PBAC, CSR, and CL will be recorded daily. After completion of study drug on cycle 2, the Crossover Study Visit will occur, during which subjects will be given a new supply of study drug for the study arm to which they will crossed over; subject diaries will be returned and coagulation studies and quality of life questionnaires performed. At 10-14 days after completion of study drug in Cycle 4, the End Study Visit will occur, during which subject diaries will be returned and quality of life questionnaires performed. All study visits will be within +/- 2 days of the scheduled visit. Study visits will be every 2 months, at the end of cycle 2 (cross-over) and at the end of cycle 4 (end of study) during which treatment diaries will be reviewed for bleeding frequency, side effects, and medications. Menstrual bleeding by PBAC, cycle severity, cycle duration, and health-related quality-of-life (HRQoL) questionnaires, including Rand Short Form 36-Question Health Survey (SF-36), Ruta Menorrhagia Severity Scale, Center for Disease Control Health-Related Quality of Life-14 Question Form (CDC-HRQoL14), and Center for Epidemiologic Studies Depression Scale (CES-D) will be assessed at baseline and after cycle 2 and after cycle 4. The study is innovative in the 1) evaluation of recombinant VWF, a new high purity recombinant VWF protein, to reduce menorrhagia, as compared with the current non-hormonal standard, tranexamic acid (TA); 2) investigation of the relationship of VWF to menstrual bleeding by PBAC score, by assessing VWD parameters: VWF ristocetin co-factor (VWF:RCo), VWF antigen (VWF:Ag), FVIII:C, VWF multimers, including high molecular weight multimers (HMW) by electrophoresis, and VWF genotype; 3) use of a "home treatment injection" for VWD; 4) comparison of two quality of life measures to assess treatment response on each study arm, one specific for bleeding disorders and one specific for menstrual disorders.

Eligibility Criteria:
Inclusion Criteria:

1. Adult females 13-45 years of age.
2. Mild or moderate von Willebrand disease (VWF:RCo \<0.50 IU/ml, normal multimers, past bleeding)
3. Menorrhagia defined as PBAC \>100 in at least one of the last two menstrual cycles.
4. Regular menses, at least every 21-35 days.
5. Willingness to have blood drawn
6. No prior history of an allergic reaction or anaphylaxis to rVWF or TA.
7. Willingness to avoid aspirin (ASA) and nonsteroidal anti-inflammatory agents (NSAIDS) during the study.
8. Willingness to comply with randomization to rVWF or TA study arms.
9. Willingness to keep a personal diary of menorrhagia bleeding frequency duration and severity by pictorial blood assessment chart, and any drugs or hemostatic agents taken.
10. Willingness to make 4 visits and undergo blood sampling for coagulation studies, and accept randomization of two therapies for each of four consecutive menstrual cycles, including an end-of-study visit.
11. Willingness to use "double-barrier" method of contraception during the study.

Exclusion Criteria:

1. Any bleeding disorder other than von Willebrand disease; or past thrombotic disease
2. Pregnant or lactating, or use of hormones (other than progesterone-only), or combined oral contraceptives, and contraceptive implants in past 3 months.
3. Platelet count \< 100,000/ul.
4. Use of immunomodulatory or experimental drugs.
5. Surgery within the past 8 weeks.
6. Concomitant use of antiplatelet drugs, anticoagulants, dextran, aspirin or NSAIDs.
7. Treatment with DDAVP, cryoprecipitate, whole blood, plasma and plasma derivatives containing VWF within 5 days of study.
8. Inability to comply with study requirements.
9. Hypothyroidism as defined by elevated TSH.
10. Iron deficiency as defined by low serum ferritin, unless iron replacement has been initiated.
11. History of renal disease