Clinical Study to Investigate the Efficacy and Safety of Wilate During Prophylaxis in Previously Treated Patients With VWD

Von Willebrand Diseases Clinical Trial

Official title:

Clinical Study to Investigate the Efficacy and Safety of Wilate During Prophylaxis in Previously Treated Patients With Von Willebrand Disease (VWD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04052698
• Other study ID #: WIL-31
• Status: Completed
• Phase: Phase 3
• Start date: June 18, 2020
• Est. completion date: April 23, 2022

Study information

• Verified date: September 2023
• Source: Octapharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a prospective, non-controlled, international, multi-center phase 3 study investigating the efficacy and safety of Wilate in previously treated adult patients with VWD, to obtain additional data on the safety and efficacy of Wilate in previously treated patients with VWD undergoing regular prophylaxis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: April 23, 2022
• Est. primary completion date: April 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

Inclusion Criteria:

Patients who meet all of the following criteria are eligible for the study:

• Aged =6 years at the time of screening

• VWD type 1 (baseline von Willebrand factor activity [VWF:Ristocetin Co-factor (RCo)] <30 IU/dL, 2A, 2B, 2M, or 3 according to medical history requiring substitution therapy with a VWF-containing product to control bleeding

• Currently receiving on-demand treatment with a VWF-containing product with at least 1, and an average of =2, documented spontaneous BEs per month in the last 6 months, with at least 2 of these BEs requiring treatment with a VWF-containing product

• Availability of records to reliably evaluate type, frequency, and treatment of BEs for at least 6 months of on-demand treatment before screening

• Female patients of child-bearing potential must have a negative urine pregnancy test at screening and agree to use adequate birth control measures; in case hormonal contra-ception is used, the medication class should remain unchanged for the duration of the study

• All patients to provide voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for the study:

• Having received on-demand or prophylactic treatment with a VWF-containing product but having no records available to reliably evaluate the type, frequency, and treatment of BEs over a period of at least 6 months of on-demand treatment

• History, or current suspicion, of VWF or FVIII inhibitors

• Medical history of a thromboembolic event within 1 year before enrolment

• Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate trans-aminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 µmol/L)

• Platelet count <100,000/µL at screening (except for VWD type 2B)

• Body weight <20 kg at screening

• Patients receiving, or scheduled to receive, immunosuppressant drugs (other than an-tiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar drugs

• Pregnant or breast-feeding at the time of enrolment

• Cervical or uterine conditions causing abnormal uterine bleeding (including infection, dysplasia)

• Treatment with any IMP in another interventional clinical study currently or within 4 weeks before enrolment

• Other coagulation disorders or bleeding disorders due to anatomical reasons

• Known hypersensitivity to any of the components of the study drug

Related Conditions & MeSH terms

• Von Willebrand Diseases

Intervention

Drug:
• Wilate
Produced from the plasma of human donors, Wilate is presented as a powder or solvent for intravenous injection containing normally 500 IU or 1000 IU human VWF and human FVIII per vial. The ratio between VWF ristocetin co-factor activity (VWF:RCo) and FVIII:C is 1:1. The product contains approximately 100 IU/ml human VWF when reconstituted with 5ml/10mL water for injection with 0.1% polysorbate 80. The specific activity of Wilate is =67 IU VWF:RCo/mg protein. The injection or infusion rate should not exceed 2-3mL per minute.

Locations

Country	Name	City	State
Belarus	Republican Research Center for Radiation Medicine and Human Ecology	Gomel
Bulgaria	"Specialized Hospital for Active Treatment of Haematological Diseases" EAD, Sofia	Sofia
Bulgaria	Pediatric Clinic of Haematology and Oncology	Varna
Croatia	University Hospital Centre Zagreb	Zagreb
Hungary	Medical Centre Hungarian Defence Forces	Budapest
Hungary	Debreceni Egyetem Klinikai Központ, Regionális Haemophilia és Thrombophilia Központ	Debrecen
Lebanon	American University of Beirut Medical Center	Beirut
Lebanon	Hotel Dieu de France Hospital	Beirut
Lebanon	Nini Hospital	Tripoli
Russian Federation	Federal State Budgetary Scientific Institution Kirov Scientific-Research Institute of Hematology and Blood Transfusion of Federal	Kirov
Russian Federation	Morosovskaya Children Clinical Hospital, Moscow Health Department, Department of General Hematology with the Pathology of Hemostasis	Moscow
Ukraine	State Institution "National Children's Specialized Hospital "OKHMATDYT" of the Ministry of Health of Ukraine," Center of Hemostasis Pathology	Kyiv
Ukraine	Communal Nonprofit Enterprise "Western Ukrainian Specialized Children's Medical Center"of Lviv Regional Council	Lviv
United States	Children's Healthcare of Atlanta	Atlanta	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Octapharma

Countries where clinical trial is conducted

United States,  Belarus,  Bulgaria,  Croatia,  Hungary,  Lebanon,  Russian Federation,  Ukraine, 

References & Publications (13)

Bodo I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J; von Willebrand factor Subcommittee of the Standardization and Scientific Committee of the International Society for Thrombosis and Haemostasis. Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH. J Thromb Haemost. 2015 Jul;13(7):1345-50. doi: 10.1111/jth.12964. Epub 2015 May 9. No abstract available. — View Citation

Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013 May;98(5):667-74. doi: 10.3324/haematol.2012.077263. — View Citation

Cella D, Yount S, Rothrock N, Gershon R, Cook K, Reeve B, Ader D, Fries JF, Bruce B, Rose M; PROMIS Cooperative Group. The Patient-Reported Outcomes Measurement Information System (PROMIS): progress of an NIH Roadmap cooperative group during its first two years. Med Care. 2007 May;45(5 Suppl 1):S3-S11. doi: 10.1097/01.mlr.0000258615.42478.55. — View Citation

Feldman BM, Funk SM, Bergstrom BM, Zourikian N, Hilliard P, van der Net J, Engelbert R, Petrini P, van den Berg HM, Manco-Johnson MJ, Rivard GE, Abad A, Blanchette VS. Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score. Arthritis Care Res (Hoboken). 2011 Feb;63(2):223-30. doi: 10.1002/acr.20353. — View Citation

Hays RD, Spritzer KL, Schalet BD, Cella D. PROMIS(R)-29 v2.0 profile physical and mental health summary scores. Qual Life Res. 2018 Jul;27(7):1885-1891. doi: 10.1007/s11136-018-1842-3. Epub 2018 Mar 22. — View Citation

Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990 Aug;97(8):734-9. doi: 10.1111/j.1471-0528.1990.tb16249.x. — 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. doi: 10.1016/0029-7844(95)00062-V. — View Citation

Maruish M. User's manual for the SF-36v2 Health Survey (3rd edition). Optum Incorporated; 2011.

Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. 2009 Aug 6;114(6):1158-65. doi: 10.1182/blood-2009-01-153296. Epub 2009 May 27. — View Citation

Sadler JE. A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1994 Apr;71(4):520-5. — View Citation

Saris-Baglama, R,DeRosa, M, Raczek, A, Bjorner, J,Turner-Bowker, D, Ware, J. The SF-10™ Health Survey for Children: A User's Guide. QualityMetric Incorporated; 2007.

U. S. Department of Health and Human Services. Health Measures. Available at http://www.healthmeasures.net/explore-measurement-systems/promis.

van Galen KPM, Timmer MA, de Kleijn P, Fischer K, Foppen W, Schutgens REG, Eikenboom J, Meijer K, Cnossen MH, Fijnvandraat K, van der Bom JG, Laros-van Gorkom BAP, Leebeek FWG, Mauser-Bunschoten EP, Win Study Group OBOT. Joint assessment in von Willebrand disease. Validation of the Haemophilia Joint Health score and Haemophilia Activities List. Thromb Haemost. 2017 Aug 1;117(8):1465-1470. doi: 10.1160/TH16-12-0967. Epub 2017 May 11. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Efficacy Rating for Wilate in Surgical Prophylaxis	Efficacy will be assessed by the surgeon at the end of surgery and by the hematologist at the end of the postoperative period using predefined criteria of 'Excellent', 'Good', 'Moderate' or 'None'. In addition, an overall assessment using the 'Excellent', 'Good', 'Moderate' or 'None' scale taking both the intra- and postoperative assessments into account will be made at the end of the postoperative period by the investigator based on an algorithm.	12 months
Other	Quality of Life (QoL) Assessed Using the Patient-Reported Outcomes Measurement Information System (PROMIS-29)	QoL assessment based on the results from the PROMIS-29 (Patient-Reported Outcomes Measurement Information System) survey, which monitors and evaluates the physical, mental, and social health in all patients. The survey covers seven domains from the most relevant areas of self-reported health (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance and ability to participate in social roles and activities) for the majority of people with chronic illness, each domain using a scale of a minimum score of 0 and a maximum score of 10. Derived T-score values are presented with higher scores equalling higher levels of the outcome being measured (e.g. more fatigue, more physical function). T-scores were calculated using the scoring service from the HealthMeasures Assessment Center. For this T-score metric 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population.	12 months
Other	Quality of Life (QoL) Assessed Using a 36-Item Short Form Health Survey, Version 2 (SF-36v2)	QoL assessment based on the results from the SF-36v2 (Short Form Health Survey) questionnaire to measure functional health and well-being in patients =16 years. SF-36v2 ranks 8 different domains using a scale standardized with a scoring algorithm to obtain a score ranging from 0 to 100. The eight health domains include physical functioning (PF), role physical (RP), bodily pain (BP), general health problems (GH), vitality (VT), social functioning (SF), role emotional (RE) and general mental health (MH). Norm-based scoring is used for the SF-36, setting the general population mean to 50 and the SD to 10 for all scales. Scores typically range from 20 to 60, with higher scores indicating better health.	12 months
Other	Quality of Life (QoL) Assessed Using a 10-Item Short Form Health Survey (SF-10)	QoL assessment based on the results from a SF-10 parent-completed questionnaire for patients =6 and <16 years of age, in order to score physical and psychosocial health. Norm-based scoring is used for the SF-36, setting the general population mean to 50 and the SD to 10 for all scales. Scores typically range from 20 to 60, with higher scores indicating better health.	12 months
Other	Joint Health Status Assessed Using Hemophilia Joint Health Score (HJHS)	Joint health status will be assessed using the Hemophilia Joint Health Score (HJHS), which has been specifically validated for the assessment of the clinical outcome in VWD. HJHS evaluates six index joints to produce a score between 0-124. The maximum score for an individual index joint is 20. Higher scores indicate worse joint health.	Baseline and 12 months
Other	Menstrual Bleeding Assessed Using Pictorial Blood Loss Assessment Chart (PBAC) Score	Bleeding information from each menstrual period while in this study will be collected using the Pictorial Blood Loss Assessment Chart (PBAC). The PBAC will be provided to all female patients of child-bearing potential. The data documented in the PBAC and the investigator-calculated final score will be recorded in the electronic case report form (eCRF). The PBAC score is from 0 onwards, with no theoretical maximum. A score of >100 defines abnormal coagulation and heavy menstrual bleeding (>80ml of blood loss per menstrual cycle).	12 months
Primary	Total Annualized Bleeding Rate (TABR)	The TABR was calculated as the total number of spontaneous bleeds, traumatic bleeds, and other bleeds (except menstrual bleeds) occurring in the time period between first dose of the investigational medicinal product (IMP) and the Study Completion Visit, divided by the duration (in years) between first dose of IMP and the Study Completion Visit.	12 months
Primary	Comparison of Total Annualized Bleeding Rates (TABR) During Prophylaxis Treatment in Study WIL-31 to On-demand Treatment in the Same Patient Population in the Preceding Study WIL-29	Estimated TABR number calculated using a negative binomial counting regression model. Comparison between this number calculated for studies WIL-29 (NCT04053699) and WIL-31. For the comparison of results from WIL-31 to WIL-29 an estimated total annualized bleeding rate was calculated for each cohort, and compared with a negative binomial counting model. As these were estimated rates, there is only one value for each cohort with no measure of spread	12 Months
Secondary	Spontaneous Annualized Bleeding Rate (SABR)	Spontaneous annualized bleeding rate (SABR) calculated in analogy with TABR	12 months
Secondary	Comparison of Spontaneous Annualized Bleeding Rates (SABR) During Prophylaxis Treatment in Study WIL-31 to On-demand Treatment in the Same Patient Population in the Preceding Study WIL-29.	Estimated SABR number calculated using a negative binomial counting regression model. Comparison between this number calculated for studies WIL-29 (NCT04053699) and WIL-31. For the comparison of results from WIL-31 to WIL-29 an estimated total annualized bleeding rate was calculated for each cohort, and compared with a negative binomial counting model. As these were estimated rates, there is only one value for each cohort with no measure of spread	12 Months
Secondary	Wilate Consumption for Prophylaxis (mFAS Population)	Data on the consumption of Wilate (VWF/FVIII IU/kg per month and per week per patient) for prophylactic treatment	12 months
Secondary	Incremental In Vivo Recovery (IVR) of Von Willebrand Factor Activity (VWF:RCo)	Incremental VWF:RCo IVR of Wilate over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treatment)	From baseline and 12-month visit
Secondary	Incremental In Vivo Recovery (IVR) of FVIII	FVIII:C of Wilate in pediatric patients (at baseline PK visit) measured by chromogenic assay	Baseline and 12-month visit
Secondary	Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs)	Treatment efficacy will be assessed at the end of a BE by the patient using predefined criteria of 'Excellent', 'Good', 'Moderate' or 'None'. All effectiveness ratings assessed as either "excellent" or "good" will be considered "successfully treated".	12 months
Secondary	Wilate Exposure for Prophylaxis (mFAS Population)	Data on the exposure days of Wilate prophylactic treatment	12 months

External Links

•   U.S Department of Health and Human Services, Health Measures