Minimize Menorrhagia in Women With Von Willebrand Disease

NCT ID: NCT02606045

Last Updated: 2024-07-01

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-07
• Study Completion Date: 2022-08-30

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.

Conditions

Von Willebrand Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group I

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 Type: ACTIVE_COMPARATOR

recombinant von Willebrand factor

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Group II

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.

Group Type: ACTIVE_COMPARATOR

recombinant von Willebrand factor

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

vonicog alfa; Vonvendi; Lysteda®

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

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

University of North Carolina

OTHER

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Margaret Ragni

OTHER

Sponsor Role: lead

Responsible Party

Margaret Ragni

Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Margaret V Ragni, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

Center for Inherited Blood Disorders (CIBD)

Orange, California, United States

University of California San Francisco

San Francisco, California, United States

Emory University Afflac Blood Disorders Center

Atlanta, Georgia, United States

Henry Ford Hospital Medical Center

Detroit, Michigan, United States

Michigan State University

East Lansing, Michigan, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University St. Louis

St Louis, Missouri, United States

Cure4thekids Foundation

Las Vegas, Nevada, United States

Rutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

State University of New York Upstate Medical Center

Syracuse, New York, United States

Cleveland Clinic Foundation

Cleveland, Ohio, United States

Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

University of Pittsburgh and Hemophilia Center Western PA

Pittsburgh, Pennsylvania, United States

Vanderbilty University

Nashville, Tennessee, United States

University of Utah

Salt Lake City, Utah, United States

Bloodworks Northwest

Seattle, Washington, United States

Versiti Blood Center of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 26843404 (View on PubMed)

Ragni MV, Rothenberger SD, Feldman R, Nance D, Leavitt AD, Malec L, Kulkarni R, Sidonio R Jr, Kraut E, Lasky J, Pruthi R, Angelini D, Philipp C, Hwang N, Wheeler AP, Seaman C, Machin N, Xavier F, Meyer M, Bellissimo D, Humphreys G, Smith KJ, Merricks EP, Nichols TC, Ivanco D, Vehec D, Koerbel G, Althouse AD. Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial. Lancet Haematol. 2023 Aug;10(8):e612-e623. doi: 10.1016/S2352-3026(23)00119-9. Epub 2023 Jun 26.

Reference Type: DERIVED

PMID: 37385272 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U01HL133815

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY19030221

Identifier Type: -

Identifier Source: org_study_id