Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A

• Sponsor: Octapharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03376516
• Collaborator: (none)
• Enrollment: 11
• Locations: 3
• Arm: 1
• Actual Duration (Months): 11.4
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

A prospective, non-controlled, international, multi-centre phase 3 study to investigate the pharmacokinetics, efficacy, safety, and immunogenicity of Wilate in previously treated children with severe haemophilia A

Condition or Disease	Intervention/Treatment	Phase
Severe Hemophilia A	Drug: Wilate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A
• Actual Study Start Date: Nov 22, 2017
• Actual Primary Completion Date: Nov 3, 2018
• Actual Study Completion Date: Nov 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All patients All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required	Drug: Wilate; von Willebrand factor / Factor VIII (plasma derived)

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC)) of FVIII:C [0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate AUC is hours (h) x international units (IU)/decilitre (dL).

2. Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Normalised (AUCNorm)) of FVIII:C for Wilate [0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The mean area under the curve normalised for the administered dose (AUCnorm) was calculated for Wilate. The units of measure used were AUC divided by dose.

3. Pharmacokinetic (PK) Assessment (Half-life (h)) of FVIII:C [0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate half-life is hours.

4. Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration) for FVIII:C [0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate]

   PK assessments of FVIII:C were determined using the one-stage (OS) assays. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. Units of measure for maximum plasma concentration are international units (IU)/ decilitre (dL)

5. Pharmacokinetic (PK) Assessment (Time to Reach Maximum Plasma Concentration (Tmax)) of FVIII:C [48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Tmax is hours (h).

6. Pharmacokinetic (PK) Assessment (Mean Residence Time (MRT)) of FVIII:C [48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate MRT is hours.

7. Pharmacokinetic (PK) Assessment (Volume of Distribution (Vd)) of FVIII:C [0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Vd is decilitre (dL)/ kilograms (kg).

8. Pharmacokinetic (PK) Assessment (Clearance) of FVIII:C [0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate]

   PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate clearance are decilitre (dL)/ hours (h)/ kilograms (kg).

9. Incremental In Vivo Recovery (IVR) of FVIII:C [48 h following a single dose of Wilate]

   The incremental IVR was determined from all patients at baseline was determined using the one-stage (OS) assay (standardised to 50 IU/kg). The units of measure to calculate IVR is kilograms (kg) / deciliter (dL)

Secondary Outcome Measures

1. Total Annualized Bleeding Rate (TABR) [6 months]

   The total number of bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of TABR.

2. Spontaneous Annualized Bleeding Rate (SABR) [6 months]

   The SABR was calculated in analogy to the TABR. The total number of spontaneous bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of the SABR.

3. Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs) [6 months]

   The proportion of BEs successfully treated with Wilate was assessed by the patient (together with the investigator in case of on-site treatment) in a patient diary. The treatment efficacy for all BEs was assessed using a pre-defined four-point scale: 'excellent', 'good', 'moderate', 'none'. '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); 'good 'was defined as "definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection, requiring up to 2 injections for complete resolution". All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated'. 'Moderate' was defined as "probable or slight beneficial effect within approximately 12 hours after the first injection" and 'none' defined as "no improvement within 12 hours, or worsening of symptoms".

4. Wilate Consumption Data: Average Dose of Wilate Per Week of Study [6 months]

   The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis

5. Incremental in Vivo Recovery (IVR) of Wilate Over Time [Baseline, and 3 and 6 months of treatment]

   The rise in FVIII:C activity in IU/dl per unit dose administered in IU/kg was determined for all patients at baseline, 3 and 6 months, using the one-stage (OS) assay.

6. Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay) [6 months]

   Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between the ABO blood type and the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.

7. Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate [6 months]

   Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between VWF:Ag with the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.

8. Safety and Tolerability of Wilate by Monitoring The Number of Adverse Events (AEs) Throughout the Study [6 months]

   At each visit (whether scheduled or unscheduled) , AEs will be documented by the investigator throughout the study. In addition, the investigator will check the patient diaries for any documented event.

9. Immunogenicity of Wilate: Number of Participants With FVIII Inhibitor Activity at 6 Months [6 months]

   FVIII inhibitor activity was determined at each study visit: screening, PK, Day 14 visit, Day 30 visit, 3 Months visit and 6 Months visit before injection.

10. Virus Safety Measured by the Number With Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study [6 months]

    Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate at the PK visit. All patients negative at screening were tested again at the Study Completion visit. The number of Parvovirus B19 seroconversions between BL and end of study was recorded

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 11 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Severe haemophilia A (<1% FVIII:C) according to medical history

2. Male patients aged 1 to <12 years

3. Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs)

4. Immunocompetence (CD4+ count >200/μL)

5. Voluntarily given, fully informed written and signed consent obtained by the patient's parent(s) or legal guardian and, depending on the children's developmental stage and intellectual capacity, informed assent by the patients before any study-related procedures are performed

The interval between the Screening Visit and the 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., inclusion criterion no. 4).

Exclusion Criteria:

1. Any coagulation disorders other than haemophilia A

2. History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory antibodies (≥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 antiretroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kirov SSC Hematology and Transfusiology	Kirov		Russian Federation
2	"National Children's Specialized Clinic "OKHMATDYT"	Kyiv		Ukraine
3	"Western Ukrainian Specialized Children's Medical Center"	Lviv		Ukraine

Sponsors and Collaborators

• Octapharma

Investigators

• Study Director: Cristina Solomon, MD, Octapharma

Study Documents (Full-Text)

• Study Protocol - Jun 19, 2017
• Statistical Analysis Plan - Jul 8, 2019

More Information

Publications

None provided.

• Responsible Party: Octapharma
• ClinicalTrials.gov Identifier: NCT03376516
• Other Study ID Numbers: WIL-30
• First Posted: Dec 18, 2017
• Last Update Posted: Jan 19, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hemophilia A

Study Results

Participant Flow

Arm/Group Title	Wilate
Arm/Group Description	A total of 11 patients were enrolled in this study. For the pharmacokinetic (PK) assessment a single dose of Wilate (50±5 IU/kg BW) was administered to 10 patients. Prophylactic treatment: Wilate (20-40 IU/kg BW) was administered every 2-3 days for 6 months. In case of unacceptably frequent spontaneous breakthrough bleeding episodes (BEs) the dose of Wilate was to be increased by approximately 5 IU/kg. The dose (and duration) of treatment for breakthrough BEs was dependent on the location and extent of bleeding and on the clinical condition of the patient; range: 10-50 IU/kg every 12-24 hours or 8-24 hours until resolved. Two patients underwent surgery treated with Wilate (SURG population). Minor surgeries received 15-30 IU/kg of Wilate every 24 hours until healing was achieved. Major surgeries were treated with 40-50 IU/kg, repeat injection every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30% to 60%.
Period Title: Overall Study
STARTED	11
Received Treatment	10
SAF Population	10
FAS Population	10
PK Population	10
PP Population	9
SURG Population	2
COMPLETED	9
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Wilate
Arm/Group Description	The safety (SAF) population includes all patients who received at least one injection of Wilate during the study (n=10).
Overall Participants	10
Age, Customized (years) [Mean (Standard Deviation) ]
1-<6 years	4.0 (1.2)
6-<12 years	9.8 (0.8)
Total	6.9 (3.2)
Sex/Gender, Customized (Count of Participants)
Female	0 0%
Male	5 50%
Female	0 0%
Male	5 50%
Female	0 0%
Male	10 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 50%
More than one race	0 0%
Unknown or Not Reported	0 0%
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 50%
More than one race	0 0%
Unknown or Not Reported	0 0%
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	10 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Weight (kg) [Mean (Standard Deviation) ]
1-<6 years	16.9 (3.6)
6-<12 years	37.4 (5.4)
Total	27.2 (11.6)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
1-<6 years	15.3 (1.3)
6-<12 years	17.7 (2.2)
Total	16.5 (2.1)
Blood groups (Count of Participants)
O	2 20%
A	1 10%
AB	0 0%
B	2 20%
O	2 20%
A	3 30%
AB	0 0%
B	0 0%
O	4 40%
A	4 40%
AB	0 0%
B	2 20%
Previous Factor (F)VIII treatment (Count of Participants)
On-demand	0 0%
Prophylaxis	3 30%
Combination	2 20%
On-demand	2 20%
Prophylaxis	0 0%
Combination	3 30%
On-demand	2 20%
Prophylaxis	3 30%
Combination	5 50%
Previous annualised bleeding rate (ABR) (Bleeding events per year (ABR)) [Mean (Standard Deviation) ]
1-<6 years	4.8 (3.0)
6-<12 years	13.6 (8.9)
Total	9.2 (7.8)

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC)) of FVIII:C
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate AUC is hours (h) x international units (IU)/decilitre (dL).
Time Frame	0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	768.8 (288.5)
6-<12 years	671.9 (289.7)
Total	720.3 (277.3)

2. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Normalised (AUCNorm)) of FVIII:C for Wilate
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The mean area under the curve normalised for the administered dose (AUCnorm) was calculated for Wilate. The units of measure used were AUC divided by dose.
Time Frame	0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	15.38 (5.77)
6-<12 years	13.44 (5.79)
Total	14.41 (5.55)

3. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Half-life (h)) of FVIII:C
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate half-life is hours.
Time Frame	0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	8.28 (1.51)
6-<12 years	9.35 (2.40)
Total	8.82 (1.97)

4. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration) for FVIII:C
Description	PK assessments of FVIII:C were determined using the one-stage (OS) assays. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. Units of measure for maximum plasma concentration are international units (IU)/ decilitre (dL)
Time Frame	0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	83.0 (16.5)
6-<12 years	78.94 (26.56)
Total	80.99 (20.94)

5. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Time to Reach Maximum Plasma Concentration (Tmax)) of FVIII:C
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Tmax is hours (h).
Time Frame	48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	0.25 (0.00)
6-<12 years	0.25 (0.00)
Total	0.25 (0.00)

6. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Mean Residence Time (MRT)) of FVIII:C
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate MRT is hours.
Time Frame	48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	11.47 (2.34)
6-<12 years	12.56 (3.53)
Total	12.01 (2.88)

7. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Volume of Distribution (Vd)) of FVIII:C
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Vd is decilitre (dL)/ kilograms (kg).
Time Frame	0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	0.784 (0.177)
6-<12 years	1.081 (0.494)
Total	0.933 (0.384)

8. Primary Outcome

Title	Pharmacokinetic (PK) Assessment (Clearance) of FVIII:C
Description	PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate clearance are decilitre (dL)/ hours (h)/ kilograms (kg).
Time Frame	0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	0.071 (0.019)
6-<12 years	0.098 (0.074)
Total	0.084 (0.053)

9. Primary Outcome

Title	Incremental In Vivo Recovery (IVR) of FVIII:C
Description	The incremental IVR was determined from all patients at baseline was determined using the one-stage (OS) assay (standardised to 50 IU/kg). The units of measure to calculate IVR is kilograms (kg) / deciliter (dL)
Time Frame	48 h following a single dose of Wilate

Outcome Measure Data

Analysis Population Description

This analysis was performed for the full-analysis (FAS) population which included all patients who has at least one injection of Wilate (n=10). The FAS population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	1-<6 Years	6-<12 Years	Total
Arm/Group Description	FAS population patients aged 1-<6 years	FAS population patients aged 6-<12 years	All patients in the FAS population.
Measure Participants	5	5	10
Mean (Standard Deviation) [kg/dL]	1.65 (0.33)	1.57 (0.53)	1.61 (0.42)

10. Secondary Outcome

Title	Total Annualized Bleeding Rate (TABR)
Description	The total number of bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of TABR.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

This analysis was performed for the full-analysis (FAS) population which included all patients who has at least one injection of Wilate (n=10). The FAS population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	FAS population
Measure Participants	10
1-<6 years	6.47 (6.61)
6-<12 years	10.62 (9.06)
Total	8.54 (7.79)

11. Secondary Outcome

Title	Spontaneous Annualized Bleeding Rate (SABR)
Description	The SABR was calculated in analogy to the TABR. The total number of spontaneous bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of the SABR.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

This analysis was performed for the full-analysis (FAS) population which included all patients who has at least one injection of Wilate (n=10). The FAS population comprised 5 patients aged 1-<6 years and 5 patients aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	FAS population
Measure Participants	10
1-<6 years	2.70 (2.93)
6-<12 years	1.20 (2.68)
Total	1.95 (2.76)

12. Secondary Outcome

Title	Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs)
Description	The proportion of BEs successfully treated with Wilate was assessed by the patient (together with the investigator in case of on-site treatment) in a patient diary. The treatment efficacy for all BEs was assessed using a pre-defined four-point scale: 'excellent', 'good', 'moderate', 'none'. '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); 'good 'was defined as "definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection, requiring up to 2 injections for complete resolution". All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated'. 'Moderate' was defined as "probable or slight beneficial effect within approximately 12 hours after the first injection" and 'none' defined as "no improvement within 12 hours, or worsening of symptoms".
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis was performed in the per-protocol (PP) population. Of the patients in the PP population, only 8 patients had evaluable bleeding events. Five of these patients were aged 1-<6 years, and 3 aged 6-<12 years.

Arm/Group Title	1-<6 Years	6-<12 Years	Total
Arm/Group Description	All patients in the PP population aged 1-<6 years.	All patients in the PP population aged 6-<12 years.	All patients in the PP population
Measure Participants	5	3	8
Measure Bleeding Events (BEs)	17	18	35
Excellent	7	9	16
Good	9	8	17
Moderate	1	1	2
None	0	0	0

13. Secondary Outcome

Title	Wilate Consumption Data: Average Dose of Wilate Per Week of Study
Description	The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The analysis was performed in the full analysis (FAS) population (total: n=10). The FAS comprised 5 patients were aged 1-<6 years and 5 were aged 6-<12 years.

Arm/Group Title	1-<6 Years	6-<12 Years	Total
Arm/Group Description	All patients in the FAS population aged 1-<6 years.	All patients in the FAS population aged 6-<12 years.	Total patients in the FAS population
Measure Participants	5	5	10
Mean (Standard Deviation) [IU/kg per week]	58.52 (14.85)	68.08 (19.02)	63.30 (16.86)

14. Secondary Outcome

Title	Incremental in Vivo Recovery (IVR) of Wilate Over Time
Description	The rise in FVIII:C activity in IU/dl per unit dose administered in IU/kg was determined for all patients at baseline, 3 and 6 months, using the one-stage (OS) assay.
Time Frame	Baseline, and 3 and 6 months of treatment

Outcome Measure Data

Analysis Population Description

The analysis was performed in the full analysis (FAS) population (total: n=10). The FAS comprised 5 patients were aged 1-<6 years and 5 were aged 6-<12 years.

Arm/Group Title	1-<6 Years	6-<12 Years	Total
Arm/Group Description	All patients in the FAS population aged 1-<6 years.	All patients in the FAS population aged 6-<12 years.	Total patients in the FAS population
Measure Participants	5	5	10
Baseline	1.65 (0.33)	1.57 (0.53)	1.61 (0.42)
3 months	1.55 (0.14)	1.56 (0.57)	1.56 (0.39)
6 months	1.63 (0.24)	1.32 (0.45)	1.48 (0.38)

15. Secondary Outcome

Title	Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)
Description	Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between the ABO blood type and the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The analysis was performed for the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-<6 years and 5 aged 6-<12 years.

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	0.185
6-<12 years	6.100
Total	0.922

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9593
	Comments	P-Value for patients aged 1-<6 years (N=5)
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3752
	Comments	P-Value for patients aged 6-<12 years (N=5)
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8273
	Comments	P-Value for total PK population (N=10)
	Method	ANOVA
	Comments

16. Secondary Outcome

Title	Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
Description	Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between VWF:Ag with the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The analysis was performed for the PK population which included all patients who underwent PK assessment during the study (total: n=10).

Arm/Group Title	Wilate
Arm/Group Description	PK population
Measure Participants	10
1-<6 years	0.121
6-<12 years	0.006
Total	0.003

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments	P-Value for patients aged 1-<6 years (N=5)
Statistical Test of Hypothesis	p-Value	0.8536
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9791
	Comments	P-Value for patients aged 6-<12 years (N=5)
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9791
	Comments	P-Value for total PK population (N=10)
	Method	ANOVA
	Comments

17. Secondary Outcome

Title	Safety and Tolerability of Wilate by Monitoring The Number of Adverse Events (AEs) Throughout the Study
Description	At each visit (whether scheduled or unscheduled) , AEs will be documented by the investigator throughout the study. In addition, the investigator will check the patient diaries for any documented event.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The safety (SAF) population included all patients who received at least one injection of Wilate during the study (n=10).

Arm/Group Title	Wilate
Arm/Group Description	The safety (SAF) population
Measure Participants	10
Number [Adverse events]	6

18. Secondary Outcome

Title	Immunogenicity of Wilate: Number of Participants With FVIII Inhibitor Activity at 6 Months
Description	FVIII inhibitor activity was determined at each study visit: screening, PK, Day 14 visit, Day 30 visit, 3 Months visit and 6 Months visit before injection.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The analysis was performed in the overall safety (SAF) population included all patients who received at least one injection of Wilate during the study (n=10). Of these, 5 patients 1-<6 years were analyzed, and 5 patients aged 6-<12 years were analyzed.

Arm/Group Title	Wilate
Arm/Group Description	FAS population
Measure Participants	10
Count of Participants [Participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Wilate
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Pearson-Copper
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; 0 to 30.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Virus Safety Measured by the Number With Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study
Description	Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate at the PK visit. All patients negative at screening were tested again at the Study Completion visit. The number of Parvovirus B19 seroconversions between BL and end of study was recorded
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Analysis was performed in all patients who underwent full analysis (FAS population) (n=10).

Arm/Group Title	Wilate
Arm/Group Description	FAS population
Measure Participants	10
Number [Participants with seroconversions]	1 10%

Adverse Events

Time Frame	Between the screening visit and the follow up contact visit (30 days after the 6-month study completion visit)
Arm/Group Title	Wilate
Arm/Group Description	The safety (SAF) population includes all patients who received at least one injection of Wilate during the study (n=10).
All Cause Mortality
	Wilate
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Wilate
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Congenital, familial and genetic disorders
Cryptochidism	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Wilate
	Affected / at Risk (%)	# Events
Total	3/10 (30%)
Infections and infestations
Respiratory tract infection	1/10 (10%)	1
Varicella	1/10 (10%)	1
Viral upper respiratory tract infection	1/10 (10%)	1
Investigations
Parvovirus B19 test positive	1/10 (10%)	1
Nervous system disorders
Headache	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.