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

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ClinicalTrials.gov Identifier: NCT02954575
Recruitment Status : Completed
First Posted : November 3, 2016
Results First Posted : December 3, 2019
Last Update Posted : January 19, 2021
Sponsor:
Information provided by (Responsible Party):
Octapharma

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Severe Hemophilia A
Intervention Drug: Wilate
Enrollment 57
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Wilate
Hide Arm/Group Description

A total of 57 patients were enrolled in the study. For the PK assessment (PK population) a single dose of Wilate of 50 ±5 IU/kg BW was administered to 21 patients.

For prophylactic treatment, Wilate was administered every 2 to 3 days at a dose of 20-40 IU/kg BW for 6 months. In case of unacceptably frequent spontaneous breakthrough BEs, the dose of Wilate was increased by approximately 5 IU/kg.

The dose (and duration) of treatment for 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.

For the surgical prophylaxis population (SURG population), minor surgeries were treated with 15-30 IU/kg every 24 hours, at least 1 day, until healing iwas 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 57
Received Treatment 55
SAF Population [1] 55
FAS Population [2] 55
PP Population [3] 52
PK Population [4] 21
SURG Population [5] 1
Completed 54
Not Completed 3
Reason Not Completed
Withdrawal by Subject             2
Adverse Event             1
[1]
SAF population = study population of patients in safety analysis
[2]
FAS population = full analysis population
[3]
PP population = per-protocol population
[4]
PK population = study population of patients who underwent pharmacokinetic analysis
[5]
SURG population = study population of patients undergoing surgery treated with Wilate
Arm/Group Title Wilate
Hide Arm/Group Description SAF population (All patients who received at least one administration of Wilate during the study (N=55)
Overall Number of Baseline Participants 55
Hide Baseline Analysis Population Description
The safety (SAF) population includes all patients who received at least one administration of Wilate during the study (N=55)
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 55 participants
35.0  (12.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants
Female
0
   0.0%
Male
55
 100.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
0
   0.0%
White
55
 100.0%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 55 participants
83.3  (21.4)
Body mass index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 55 participants
26.8  (5.8)
Blood groups  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants
0
19
  34.5%
A
23
  41.8%
AB
5
   9.1%
B
8
  14.5%
von Willebrand factor antigen (VWF:Ag)   [1] 
Mean (Standard Deviation)
Unit of measure:  IU/dL
Number Analyzed 55 participants
118.4  (78.9)
[1]
Measure Description: Plasma VWF:Ag measurements recorded at baseline
von Willebrand factor activity (VWF:Ac)   [1] 
Mean (Standard Deviation)
Unit of measure:  IU/dL
Number Analyzed 55 participants
103.7  (39.5)
[1]
Measure Description: Plasma VWF:Ac measurements recorded at baseline
Previous Factor (F) VIII treatment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants
On-demand
32
  58.2%
Prophylaxis
18
  32.7%
Combination
5
   9.1%
Previous annualized bleeding rate (ABR)   [1] 
Mean (Standard Deviation)
Unit of measure:  No. BEs per patient per year
Number Analyzed 55 participants
32.98  (39.12)
[1]
Measure Description: Previous ABR is based on the bleeding rate in the 6 months prior to entry into the study.
1.Primary Outcome
Title Total Annualized Bleeding Rate (TABR)
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The total annualized bleeding rate (TABR) was calculated for all patients included in the PP population (N=52).
Arm/Group Title Wilate
Hide Arm/Group Description:
PP population
Overall Number of Participants Analyzed 52
Overall Number of Units Analyzed
Type of Units Analyzed: No. of Bleeding Episodes (BEs)
57
Mean (Standard Deviation)
Unit of Measure: No. of BEs / year (ABR)
2.10  (3.44)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wilate
Comments A confirmative one-sided, one-sample Poisson test was used to test whether the mean annualized bleeding rate (ABR) in patients treated prophylactically with Wilate was below the threshold of 29 BEs per patient year (alpha = 2.5%). This threshold corresponds to 50% of the TABR reported in the GENA-01 study (NCT00989196), which observed 58.1 BEs per patient per year. A corresponding two-sided 95% CI for the TABR was also analyzed.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments versus mean TABR >29
Method Poisson test estimate
Comments [Not Specified]
Method of Estimation Estimation Parameter Poisson test estimate
Estimated Value 2.13
Confidence Interval (2-Sided) 95%
1.64 to 2.76
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Spontaneous Annualized Bleeding Rate (SABR)
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The spontaneous annualized bleeding rate (SABR) was calculated for all patients included in the PP population (N=52).
Arm/Group Title Wilate
Hide Arm/Group Description:
PP population
Overall Number of Participants Analyzed 52
Overall Number of Units Analyzed
Type of Units Analyzed: No. of BEs
41
Mean (Standard Deviation)
Unit of Measure: No. of spontaneous BEs/year (SABR)
1.51  (3.03)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wilate
Comments A confirmative one-sided, one-sample Poisson test was used to test whether the mean SABR in patients treated prophylactically with Wilate was below the threshold of 19.1 BEs per patient year (alpha = 2.5%). This threshold corresponds to 50% of the SABR in the GENA-01 study (NCT00989196), which observed 38.2 spontaneous BEs per patient per year. A corresponding two-sided 95% CI for the SABR was also analyzed.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments versus mean SABR >19.1
Method Poisson test estimate
Comments [Not Specified]
Method of Estimation Estimation Parameter Poisson test estimate
Estimated Value 1.53
Confidence Interval (2-Sided) 95%
1.13 to 2.08
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Efficacy of Wilate in the Treatment of Breakthrough BEs
Hide Description 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.'
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the PP population, efficacy of Wilate in the treatment of breakthrough BEs was analyzed for all patients experiencing breakthrough BEs (N=24)
Arm/Group Title Wilate
Hide Arm/Group Description:
Efficacy of Wilate was analysed for the PP population
Overall Number of Participants Analyzed 24
Overall Number of Units Analyzed
Type of Units Analyzed: Number of BEs
57
Count of Units
Unit of Measure: Number of BEs
Excellent
16
  28.1%
Good
32
  56.1%
Moderate
9
  15.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wilate
Comments

Confirmatory statistical testing tested the null hypotheses that the percentage of success is ≤70% (alternative hypothesis: percentage >70%); the test procedure based on the generalized estimation equation took into account several BEs in one patient as correlated repeated measurements (alpha = 2.5%). Thus, π denotes the proportion of success and the following pair of hypotheses was tested:

H0: π ≤ 0.7 vs. H1: π > 0.7

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0096
Comments [Not Specified]
Method Confirmatory data analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Generalized estimation equation
Estimated Value 84.21
Confidence Interval (2-Sided) 95%
72.13 to 92.52
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis
Hide Description The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
PP population
Overall Number of Participants Analyzed 52
Mean (Standard Deviation)
Unit of Measure: IU/kg
405.06  (83.70)
5.Secondary Outcome
Title Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C
Hide Description 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.
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
AUC divided by dose (IU*h/dL per IU/kg)
Arm/Group Title Wilate
Hide Arm/Group Description:
PK population
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: IU*h/dL per IU/kg
Initial PK 28.61  (9.31)
PK completion 6 months 30.75  (11.32)
6.Secondary Outcome
Title Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C
Hide Description 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.
Time Frame 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
PK population
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: Hours
Initial PK 10.82  (2.50)
PK completion 6 months 11.50  (2.30)
7.Secondary Outcome
Title Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C
Hide Description 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.
Time Frame Initial PK assessment (Day -1) and 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
PK population
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: IU/dL
Initial PK 106.70  (22.45)
PK completion 6 months 103.49  (26.53)
8.Secondary Outcome
Title Incremental in Vivo Recovery (IVR) of Wilate Over Time
Hide Description 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.
Time Frame Baseline, 3 and 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
FAS population
Overall Number of Participants Analyzed 55
Mean (Standard Deviation)
Unit of Measure: kg/dL
First PK/non-PK visit 2.14  (0.51)
3 months 2.14  (0.49)
PK/non-PK completion 6 months 1.97  (0.64)
9.Secondary Outcome
Title Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
PK population
Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: Beta coefficient
15.867
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wilate
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0346
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
10.Secondary Outcome
Title Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
PK population
Overall Number of Participants Analyzed 21
Measure Type: Number
Unit of Measure: Beta coefficient
5.104
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wilate
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4244
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
11.Secondary Outcome
Title Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study
Hide Description At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the FAS population (N=55), the safety and tolerability of Wilate was analysed for all patients experiencing adverse events (AEs) throughout the study.
Arm/Group Title Wilate
Hide Arm/Group Description:
FAS population
Overall Number of Participants Analyzed 55
Measure Type: Number
Unit of Measure: Number of adverse events
Number of AEs 17
Number of Treatment-emergent AEs 16
12.Secondary Outcome
Title Immunogenicity of Wilate by Testing for FVIII Inhibitors
Hide Description FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification).
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
FAS population
Overall Number of Participants Analyzed 55
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Wilate
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Pearson-Copper
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 16.11
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Virus Safety Measured by the Number of Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
In the FAS population (N=55), the viral safety of Wilate was analyzed for all patients at baseline.
Arm/Group Title Wilate
Hide Arm/Group Description:
FAS population
Overall Number of Participants Analyzed 55
Measure Type: Number
Unit of Measure: Participants
0
14.Other Pre-specified Outcome
Title Efficacy of Wilate in Surgical Prophylaxis
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Wilate
Hide Arm/Group Description:
SURG population (study population of patients undergoing surgery treated with Wilate)
Overall Number of Participants Analyzed 1
Measure Type: Count of Participants
Unit of Measure: Participants
Excellent
0
   0.0%
Good
1
 100.0%
Moderate
0
   0.0%
None
0
   0.0%
Time Frame 6 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Wilate
Hide Arm/Group Description SAF population
All-Cause Mortality
Wilate
Affected / at Risk (%)
Total   0/55 (0.00%)    
Hide Serious Adverse Events
Wilate
Affected / at Risk (%) # Events
Total   0/55 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Wilate
Affected / at Risk (%) # Events
Total   12/55 (21.82%)    
Blood and lymphatic system disorders   
Thrombocytosis  [1]  2/55 (3.64%)  2
General disorders   
Pain  [1]  1/55 (1.82%)  1
Immune system disorders   
Seasonal allergy  [1]  2/55 (3.64%)  2
Infections and infestations   
Erysipelas  [1]  1/55 (1.82%)  1
Nasopharyngitis  [1]  1/55 (1.82%)  1
Viral upper respiratory tract infection  [1]  1/55 (1.82%)  1
Injury, poisoning and procedural complications   
Limb injury  [1]  1/55 (1.82%)  1
Musculoskeletal and connective tissue disorders   
Arthralgia  [1]  2/55 (3.64%)  5
Nervous system disorders   
Headache  [1]  1/55 (1.82%)  1
Skin and subcutaneous tissue disorders   
Eczema  [1]  1/55 (1.82%)  1
Indicates events were collected by systematic assessment
[1]
Treatment-emergent adverse event
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Cristina Solomon
Organization: Octapharma AG
Phone: +41 (0)55 451 21 89
EMail: Cristina.Solomon@octapharma.com
Layout table for additonal information
Responsible Party: Octapharma
ClinicalTrials.gov Identifier: NCT02954575    
Other Study ID Numbers: WIL-27
First Submitted: October 27, 2016
First Posted: November 3, 2016
Results First Submitted: March 20, 2019
Results First Posted: December 3, 2019
Last Update Posted: January 19, 2021