Von Willebrand Factor in Pregnancy (VIP) Study

Von Willebrand Diseases Clinical Trial

— VIP  

Official title:

Von Willebrand Factor in Pregnancy (VIP) Study: A Multicenter Study of Wilate Use in Von Willebrand Disease for Childbirth

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04146376
• Other study ID #: VIPStudy
• Status: Recruiting
• Start date: October 12, 2019
• Est. completion date: June 2023

Study information

• Verified date: January 2021
• Source: Bloodworks
• Contact: Sarah Ruuska, MPH
• Phone: 206-689-6193
• Email: sarahru[@]bloodworksnw.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

In pregnant women with von Willebrand disease (VWD) who by the third trimester do not have von Willebrand factor (VWF) or factor VIII (FVIII) levels greater than 50-100%, specific guidance is lacking for delivery planning in terms of how high of a VWF level should be achieved to reduce bleeding.

This is a prospective, open-label, cohort study in women with VWD using Wilate VWF replacement therapy to maintain trough or minimum VWF levels of 100-150% for delivery and the immediate postpartum period, followed by levels of 50-100% for 5-10 days after delivery, depending upon the route of delivery. The primary objective is to document the rate of primary postpartum hemorrhage (PPH). The secondary objective is to document further effectiveness outcomes and safety.

Description:

For pregnant women with von Willebrand disease (VWD) who by the third trimester do not have von Willebrand factor (VWF) or factor VIII (FVIII) levels > 50-100%, specific guidance is lacking for delivery planning for how high a VWF level should be achieved. Specifically, guidance is lacking on whether VWF replacement therapy should target a VWF minimum level in the 100-150% range, i.e., a range closer to the 200-250% levels observed in normal pregnancy.

This is a prospective, open-label, cohort study using Wilate VWF replacement therapy, trough or minimum VWF levels of 100-150% will be maintained for delivery in women with VWD whose third trimester VWF levels are <100%. This group is termed "non-correctors". Women with VWD whose third trimester VWF levels spontaneously rise to >100% will be assigned to the "corrector" group, and these women will not receive VWF replacement therapy. All patients will receive tranexamic acid for 14 days postpartum. Outcome parameters will be assessed for all patients.

The investigators or qualified research personnel will approach all consecutive pregnant VWD patients until 65 non-corrector patients have completed the study protocol, and up to 30 corrector patients have completed the study protocol. Patients with gestational week 34-38 von Willebrand factor activity (VWF:Act) or von Willebrand factor ristocetin cofactor (VWF:RCo), and/or Factor VIII procoagulant activity (FVIII:C) less than 100 percent will be used to assign patients to the non-corrector group. When VWF collagen binding (VWF:CB) laboratory monitoring can be performed, patients with an isolated VWF:CB type 2 defect can also be enrolled.

Rate of primary postpartum hemorrhage, severe postpartum hemorrhage, secondary postpartum hemorrhage will be measured. Safety and secondary laboratory measures will be assessed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: June 2023
• Est. primary completion date: June 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• von Willebrand Disease (VWD) patients defined prepartum as Type 1 per National Heart, Lung, and Blood Institute (NHLBI) criterion of von Willebrand Factor (VWF) level less than 30 percent, or Type 2, or Type 3

• VWF and Factor VIII (FVIII) levels obtained in gestational weeks 34-38 will determine enrollment in the non-corrector or corrector group:

• Patients with gestational week 34-38 VWF:Ag, VWF:Act (or VWF:RCo), or FVIII:Act less than 100 percent will be enrolled in the non-corrector group. In patients with an isolated VWF:CB type 2 defect, VWF:CB less than 100 percent can also be determined as a non-corrector

• Patients with VWF parameter levels greater than or equal to 100 percent self-corrected at gestational weeks 34-38 will be enrolled in the corrector group

• Written informed consent from the patient prepartum, before gestational week 39

Exclusion Criteria:

• Presence of other concurrent disorder of hemostasis, platelet dysfunction, or collagen disorders

• Presence of liver disease or renal disease, clinical suspicion or diagnosis of preeclampsia or eclampsia, HELLP syndrome, TTP, DIC, or other acquired vasculopathy or coagulopathy

• Age less than 18 years

• Inability of the local laboratory to monitor the VWF laboratory tests needed during the course of treatment to determine Wilate dosing adjustments

Related Conditions & MeSH terms

• Von Willebrand Diseases

Intervention

Other:
• Use of a postpartum diary and additional blood draws
A diary will be used to capture postpartum hemorrhage (PPH), Wilate and tranexamic acid use, other drug use, bleeding episodes, and treatment schedules. Several blood draws additional to what is expected for routine clinical care will also be taken.

Drug:
• VWF replacement therapy with Wilate
This study design uses on-label Wilate for VWF replacement therapy for delivery and the postpartum period in VWD patients whose VWF levels are <100% in the third trimester of pregnancy
• Tranexamic acid
This study design uses tranexamic acid for prophylaxis for postpartum hemorrhage for all women with VWD

Other:
• Use of a postpartum diary and additional blood draws.
A diary will be used to capture postpartum hemorrhage (PPH), tranexamic acid use, other drug use, bleeding episodes, and treatment schedules. Several blood draws additional to what is expected for routine clinical care will also be taken.

Locations

Country	Name	City	State
United States	Tulane University School of Medicine, Louisiana Center for Bleeding and Clotting Disorders	New Orleans	Louisiana
United States	Bleeding & Clotting Disorders Institute	Peoria	Illinois
United States	Washington Center for Bleeding Disorders at Bloodworks	Seattle	Washington

Sponsors (4)

Lead Sponsor	Collaborator
Bloodworks	Ergomed, Mary M. Gooley Hemophilia Center, Octapharma

Country where clinical trial is conducted

United States, 

References & Publications (18)

Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009 Dec;114(6):1326-1331. doi: 10.1097/AOG.0b013e3181c2bde8. Review. Erratum in: Obstet Gynecol. 2010 Feb;115(2 Pt 1):387. — View Citation

Demers C, Derzko C, David M, Douglas J; Society of Obstetricians and Gynecologists of Canada. Gynaecological and obstetric management of women with inherited bleeding disorders. J Obstet Gynaecol Can. 2005 Jul;27(7):707-32. English, French. — View Citation

Drury-Stewart DN, Lannert KW, Chung DW, Teramura GT, Zimring JC, Konkle BA, Gammill HS, Johnsen JM. Complex changes in von Willebrand factor-associated parameters are acquired during uncomplicated pregnancy. PLoS One. 2014 Nov 19;9(11):e112935. doi: 10.1371/journal.pone.0112935. eCollection 2014. — View Citation

Govorov I, Löfgren S, Chaireti R, Holmström M, Bremme K, Mints M. Postpartum Hemorrhage in Women with Von Willebrand Disease - A Retrospective Observational Study. PLoS One. 2016 Oct 25;11(10):e0164683. doi: 10.1371/journal.pone.0164683. eCollection 2016. Erratum in: PLoS One. 2017 Feb 9;12 (2):e0172185. — View Citation

Hawke L, Grabell J, Sim W, Thibeault L, Muir E, Hopman W, Smith G, James P. Obstetric bleeding among women with inherited bleeding disorders: a retrospective study. Haemophilia. 2016 Nov;22(6):906-911. doi: 10.1111/hae.13067. Epub 2016 Oct 5. — View Citation

Huq FY, Kulkarni A, Agbim EC, Riddell A, Tuddenham E, Kadir RA. Changes in the levels of factor VIII and von Willebrand factor in the puerperium. Haemophilia. 2012 Mar;18(2):241-5. doi: 10.1111/j.1365-2516.2011.02625.x. Epub 2011 Sep 28. — View Citation

James AH, Cooper DL, Paidas MJ. A global quantitative survey of hemostatic assessment in postpartum hemorrhage and experience with associated bleeding disorders. Int J Womens Health. 2017 Jul 3;9:477-485. doi: 10.2147/IJWH.S132135. eCollection 2017. — View Citation

James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. J Thromb Haemost. 2007 Jun;5(6):1165-9. — View Citation

James AH, Konkle BA, Kouides P, Ragni MV, Thames B, Gupta S, Sood S, Fletcher SK, Philipp CS. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis. Haemophilia. 2015 Jan;21(1):81-7. doi: 10.1111/hae.12568. Epub 2014 Oct 21. — View Citation

Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol. 1995 Jun;85(6):977-82. — View Citation

Kirtava A, Drews C, Lally C, Dilley A, Evatt B. Medical, reproductive and psychosocial experiences of women diagnosed with von Willebrand's disease receiving care in haemophilia treatment centres: a case-control study. Haemophilia. 2003 May;9(3):292-7. — View Citation

Kouides PA. Present day management of inherited bleeding disorders in pregnancy. Expert Rev Hematol. 2016 Oct;9(10):987-95. doi: 10.1080/17474086.2016.1216312. Epub 2016 Aug 2. Review. — View Citation

Kujovich JL. von Willebrand disease and pregnancy. J Thromb Haemost. 2005 Feb;3(2):246-53. Review. — View Citation

Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014 Nov;167(4):453-65. doi: 10.1111/bjh.13064. Epub 2014 Aug 12. Review. — View Citation

Mannucci PM, Franchini M, Castaman G, Federici AB; Italian Association of Hemophilia Centers. Evidence-based recommendations on the treatment of von Willebrand disease in Italy. Blood Transfus. 2009 Apr;7(2):117-26. doi: 10.2450/2008.0052-08. — View Citation

Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008 Mar;14(2):171-232. doi: 10.1111/j.1365-2516.2007.01643.x. — View Citation

Stoof SC, van Steenbergen HW, Zwagemaker A, Sanders YV, Cannegieter SC, Duvekot JJ, Leebeek FW, Peters M, Kruip MJ, Eikenboom J. Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey. Haemophilia. 2015 Jul;21(4):505-12. doi: 10.1111/hae.12635. Epub 2015 Feb 16. — View Citation

Szecsi PB, Jørgensen M, Klajnbard A, Andersen MR, Colov NP, Stender S. Haemostatic reference intervals in pregnancy. Thromb Haemost. 2010 Apr;103(4):718-27. doi: 10.1160/TH09-10-0704. Epub 2010 Feb 19. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	occurrence of venous or arterial thrombus	clinically documented venous or arterial thrombus	up to 42 days postpartum
Other	occurrence of infusion-related reactions	clinically documented infusion-related reactions	up to 42 days postpartum
Other	laboratory assessment of efficacy and VWF replacement	central laboratory assessment of VWF parameters relative to bleeding	up to 42 days postpartum
Primary	rate of primary postpartum hemorrhage (PPH)	estimated blood loss greater than or equal to 1000 mL, or severe PPH defined as estimated blood loss greater than 2000 mL within 24 hours postpartum, as indicated by: visual estimation, pre- and post- weight of blood soaked materials, photospectrometry	within 24 hours postpartum
Secondary	rate of secondary postpartum hemorrhage (PPH)	excessive blood loss: any transfusions not anticipated in the antepartum birth plan, including number and type of blood products transfused within 48 hours after treatment, any transfusions not anticipated in the antepartum birth plan, including number and type of blood products transfused beyond 48 hours after treatment, change in antepartum hemoglobin, change in pictorial blood assessment chart (PBAC) score, number of patients needing interventions for bleeding (e.g., use of Bakri balloon, angiographic embolization, B-Lynch sutures, surgical arterial ligation, or hysterectomy for persistent bleeding), iron levels (serum iron, TIBC, and ferritin) 6 weeks postpartum	24 hours to 6 weeks postpartum