Minimize Menorrhagia in Women With Von Willebrand Disease

Von Willebrand Diseases Clinical Trial

— VWDMin  

Official title:

Prospective, Randomized, Crossover Trial Comparing Recombinant Von Willebrand Factor (rVWF) vs. Tranexamic Acid (TA) to Minimize Menorrhagia in Women With Von Willebrand Disease: The VWD Minimize Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02606045
• Other study ID #: STUDY19030221
• Secondary ID: U01HL133815
• Status: Terminated
• Phase: Phase 3
• Start date: February 7, 2019
• Est. completion date: August 30, 2022

Study information

• Verified date: February 2024
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 36
• Est. completion date: August 30, 2022
• Est. primary completion date: April 30, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 13 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Menorrhagia
• Von Willebrand Diseases

Intervention

Drug:
• recombinant von Willebrand factor
Group I will receive Arm A recombinant von Willebrand factor 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. 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.
• tranexamic acid
Group I will receive Arm A recombinant von Willebrand factor 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. 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.

Locations

Country	Name	City	State
United States	Emory University Afflac Blood Disorders Center	Atlanta	Georgia
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Henry Ford Hospital Medical Center	Detroit	Michigan
United States	Michigan State University	East Lansing	Michigan
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Cure4thekids Foundation	Las Vegas	Nevada
United States	Versiti Blood Center of Wisconsin	Milwaukee	Wisconsin
United States	Vanderbilty University	Nashville	Tennessee
United States	Rutgers Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Center for Inherited Blood Disorders (CIBD)	Orange	California
United States	University of Pittsburgh and Hemophilia Center Western PA	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University St. Louis	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of California San Francisco	San Francisco	California
United States	Bloodworks Northwest	Seattle	Washington
United States	State University of New York Upstate Medical Center	Syracuse	New York

Sponsors (4)

Lead Sponsor	Collaborator
Margaret Ragni	Duke University, National Heart, Lung, and Blood Institute (NHLBI), University of North Carolina

Country where clinical trial is conducted

United States, 

References & Publications (1)

Ragni MV, Machin N, Malec LM, James AH, Kessler CM, Konkle BA, Kouides PA, Neff AT, Philipp CS, Brambilla DJ. Von Willebrand factor for menorrhagia: a survey and literature review. Haemophilia. 2016 May;22(3):397-402. doi: 10.1111/hae.12898. Epub 2016 Feb 4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Menstrual Bleeding Severity	Bleeding severity measured by pictorial bleeding assessment chart (PBAC).	24 weeks
Secondary	Menstrual bleeding unresponsive to study drugs	Menorrhagia cycle severity rating by patient diary, cycle length by PBAC, drug logs	24 weeks
Secondary	Quality of life including depression, wellness, activity	Quality of life questionnaires (HRQoL): Rand Short Form 36-Question Health Survey (SF-36), Ruta Menorrhagia Score, Center for Disease Control Health-Related Quality of Life 14 Questions (CDC-HRQoL-14), and Center for Epidemiology Studies Depression Scale (CES-D), and Satisfaction Survey	24 weeks
Secondary	von Willebrand assays, genotype	von Willebrand assays: VWF ristocetin cofactor (VWF:RCo), VWF antigen ( VWF:Ag), VIII:C, multimers; VWF genotype	24 weeks