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Minimize Menorrhagia in Women With Von Willebrand Disease (VWDMin)

Primary Purpose

Von Willebrand Diseases

Status
Active
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
recombinant von Willebrand factor
tranexamic acid
Sponsored by
Margaret Ragni
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Von Willebrand Diseases focused on measuring menorrhagia, VWD

Eligibility Criteria

13 Years - 45 Years (Child, Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Banner MD Anderson Cancer Center
  • Center for Inherited Blood Disorders (CIBD)
  • University of California San Francisco
  • Emory University Afflac Blood Disorders Center
  • Henry Ford Hospital Medical Center
  • Michigan State University
  • Mayo Clinic
  • Washington University St. Louis
  • Cure4thekids Foundation
  • Rutgers Robert Wood Johnson Medical School
  • State University of New York Upstate Medical Center
  • Cleveland Clinic Foundation
  • Ohio State University Wexner Medical Center
  • Oregon Health and Science University
  • University of Pittsburgh and Hemophilia Center Western PA
  • Vanderbilty University
  • University of Utah
  • Bloodworks Northwest
  • Versiti Blood Center of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Group I

Group II

Arm Description

Subjects randomized to 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, tranexamic acid 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, tranexamic acid 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, recombinant von Willebrand factor 40 IU/kg intravenously (IV) infusion on day 1 on each of two menstrual cycles, Cycles 3 and 4.

Outcomes

Primary Outcome Measures

Menstrual Bleeding Severity
Bleeding severity measured by pictorial bleeding assessment chart (PBAC).

Secondary Outcome Measures

Menstrual bleeding unresponsive to study drugs
Menorrhagia cycle severity rating by patient diary, cycle length by PBAC, drug logs
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
von Willebrand assays, genotype
von Willebrand assays: VWF ristocetin cofactor (VWF:RCo), VWF antigen ( VWF:Ag), VIII:C, multimers; VWF genotype

Full Information

First Posted
November 5, 2015
Last Updated
June 2, 2023
Sponsor
Margaret Ragni
Collaborators
University of North Carolina, Duke University, National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02606045
Brief Title
Minimize Menorrhagia in Women With Von Willebrand Disease
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 7, 2019 (Actual)
Primary Completion Date
March 21, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Margaret Ragni
Collaborators
University of North Carolina, Duke University, National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Von Willebrand Diseases
Keywords
menorrhagia, VWD

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group I
Arm Type
Active Comparator
Arm Description
Subjects randomized to 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, tranexamic acid 650 mg 2 tablets orally (po) three times daily on days 1-5 of each of two menstrual cycles, Cycles 3 and 4.
Arm Title
Group II
Arm Type
Active Comparator
Arm Description
Group II will receive Arm B, tranexamic acid 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, recombinant von Willebrand factor 40 IU/kg intravenously (IV) infusion on day 1 on each of two menstrual cycles, Cycles 3 and 4.
Intervention Type
Drug
Intervention Name(s)
recombinant von Willebrand factor
Other Intervention Name(s)
vonicog alfa, Vonvendi
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
tranexamic acid
Other Intervention Name(s)
Lysteda®
Intervention Description
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.
Primary Outcome Measure Information:
Title
Menstrual Bleeding Severity
Description
Bleeding severity measured by pictorial bleeding assessment chart (PBAC).
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Menstrual bleeding unresponsive to study drugs
Description
Menorrhagia cycle severity rating by patient diary, cycle length by PBAC, drug logs
Time Frame
24 weeks
Title
Quality of life including depression, wellness, activity
Description
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
Time Frame
24 weeks
Title
von Willebrand assays, genotype
Description
von Willebrand assays: VWF ristocetin cofactor (VWF:RCo), VWF antigen ( VWF:Ag), VIII:C, multimers; VWF genotype
Time Frame
24 weeks

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
13 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult females 13-45 years of age. Mild or moderate von Willebrand disease (VWF:RCo <0.50 IU/ml, normal multimers, past bleeding) Menorrhagia defined as PBAC >100 in at least one of the last two menstrual cycles. Regular menses, at least every 21-35 days. Willingness to have blood drawn No prior history of an allergic reaction or anaphylaxis to rVWF or TA. Willingness to avoid aspirin (ASA) and nonsteroidal anti-inflammatory agents (NSAIDS) during the study. Willingness to comply with randomization to rVWF or TA study arms. 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. 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. Willingness to use "double-barrier" method of contraception during the study. Exclusion Criteria: Any bleeding disorder other than von Willebrand disease; or past thrombotic disease Pregnant or lactating, or use of hormones (other than progesterone-only), or combined oral contraceptives, and contraceptive implants in past 3 months. Platelet count < 100,000/ul. Use of immunomodulatory or experimental drugs. Surgery within the past 8 weeks. Concomitant use of antiplatelet drugs, anticoagulants, dextran, aspirin or NSAIDs. Treatment with DDAVP, cryoprecipitate, whole blood, plasma and plasma derivatives containing VWF within 5 days of study. Inability to comply with study requirements. Hypothyroidism as defined by elevated TSH. Iron deficiency as defined by low serum ferritin, unless iron replacement has been initiated. History of renal disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Margaret V Ragni, MD, MPH
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
Banner MD Anderson Cancer Center
City
Gilbert
State/Province
Arizona
ZIP/Postal Code
85234
Country
United States
Facility Name
Center for Inherited Blood Disorders (CIBD)
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94117
Country
United States
Facility Name
Emory University Afflac Blood Disorders Center
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Henry Ford Hospital Medical Center
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Michigan State University
City
East Lansing
State/Province
Michigan
ZIP/Postal Code
48824
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55902
Country
United States
Facility Name
Washington University St. Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Cure4thekids Foundation
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89135
Country
United States
Facility Name
Rutgers Robert Wood Johnson Medical School
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
Facility Name
State University of New York Upstate Medical Center
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
University of Pittsburgh and Hemophilia Center Western PA
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Vanderbilty University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37322
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Bloodworks Northwest
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
Versiti Blood Center of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The IPD to be shared include individual bleeding data (PBAC), cycle severity score (CSR), cycle length (CL), quality of life by four scales (SF-36, Ruta, CDC-HRQoL-14, CES-D), satisfaction survey, VWF assays, VWF genotype.
IPD Sharing Time Frame
Within 12 months of trial completion.
IPD Sharing Access Criteria
Qualified investigators will have access to data and bio specimens, consistent with data sharing policies and applicable laws, and upon receipt of a Research Materials Distribution Agreement, data will be transferred by secure transfers through the BioLINCC website.
Citations:
PubMed Identifier
26843404
Citation
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.
Results Reference
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Minimize Menorrhagia in Women With Von Willebrand Disease

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