Minimize Menorrhagia in Women With Von Willebrand Disease
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.
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