Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A

Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Patients With Severe Hemophilia A

The purpose of this study is to obtain additional data on the safety and efficacy of Wilate in PTPs with hemophilia A with at least 150 previous exposure days (EDs) to a FVIII concentrate who undergo prophylactic treatment with Wilate for 6 months and at least 50 EDs, thus supplementing the existing database to obtain approval of Wilate for the indication hemophilia A in the USA.

Study Overview

• Status: Completed
• Conditions: Severe Hemophilia A
• Intervention / Treatment: Drug: Wilate

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria
    • Specialized Hospital for Active Treatment "Joan Pavel"
• Hungary
  • Budapest, Hungary
    • National Haemophilia Centre
• Poland
  • Krakow, Poland
    • Krakowskie Centrum Medyczne
  • Rzeszow, Poland
    • Korczowski Bartosz Gabinet Lekarski
• Romania
  • Bucharest, Romania
    • Centrul Medical Unirea -Policlinica Enescu
• Russian Federation
  • Barnaul, Russian Federation
    • Barnaul Branch of RAMS hematology center
  • Moscow, Russian Federation
    • Federal Scientific Hematology Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Severe hemophilia A (<1% FVIII:C) according to medical history
2. Male patients aged ≥12 years
3. Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs)
4. Immunocompetence (CD4+ count >200/µL)
5. Good documentation of the historical bleeding rate (at least for the 6 months preceding study start)
6. Voluntarily given, fully informed written and signed consent obtained by the patient (or parent/legal guardian in case of adolescents) before any study-related procedures are conducted

Whenever possible, the interval between the Screening Visit and the PK or Non-PK Visit should not exceed 30 days. If the 30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be >200/µL for patients to be enrolled (i.e., exclusion criterion no. 4).

Exclusion Criteria:

1. Any coagulation disorders other than hemophilia A
2. History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory anti-bodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as determined by the central laboratory
3. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate transaminase [ASAT] levels >5 times of upper limit of normal, creatinine>120 µmol/L)
4. Patients receiving or scheduled to receive immunomodulating drugs (other than anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
5. Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: All patients; All patients will receive Wilate for prophylactic treatment	Drug: Wilate; Other Names: von Willebrand factor / Factor VIII (plasma derived)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Annualized Bleeding Rate (TABR)	The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spontaneous Annualized Bleeding Rate (SABR)	The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.	6 months
Efficacy of Wilate in the Treatment of Breakthrough BEs	The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where 'excellent' was defined as "Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection" (best outcome) and 'none' was defined as "No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution" (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.'	6 months
Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis	The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis.	6 months
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C	PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.	Initial PK visit (Day -1) and PK study completion visit (6 months); data collected 1 h prior to injection and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection
Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C	PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.	Initial PK assessment (Day -1) and PK study completion visit (6 months); data collected 1 h prior to infusion and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C	PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.	Initial PK assessment (Day -1) and 6 months
Incremental in Vivo Recovery (IVR) of Wilate Over Time	The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the OS assay.	Baseline, 3 and 6 months
Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)	Analysis of variance (ANOVA) was used in an exploratory sense to assess an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.	6 months
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate	ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.	6 months
Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study	At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.	6 months
Immunogenicity of Wilate by Testing for FVIII Inhibitors	FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification).	6 months
Virus Safety Measured by the Number of Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study	Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of Wilate in Surgical Prophylaxis	Hemostatic efficacy was assessed at the end of surgery by the surgeon and at end of the postoperative period by the hematologist, using a 4-point hemostatic efficacy scale including the four items: 'excellent' (best possible outcome), 'good', 'moderate' and 'none' (worst outcome). Overall efficacy was assessed by the investigator, taking both the intra and postoperative assessments into account, and using the 'excellent,' 'good,' moderate,' and 'none' scale.	6 months

Collaborators and Investigators

• Sponsor: Octapharma

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): March 29, 2018
• Study Completion (Actual): March 29, 2018

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: November 1, 2016
• First Posted (Estimate): November 3, 2016

Study Record Updates

• Last Update Posted (Actual): January 19, 2021
• Last Update Submitted That Met QC Criteria: December 21, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: WIL-27

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No