We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Assess the Efficacy and Safety of Personalized Prophylaxis Human-cl rhFVIII in Patients With Severe Haemophilia A

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02256917
Recruitment Status : Completed
First Posted : October 6, 2014
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: Prevention
Condition Severe Haemophilia A
Intervention Biological: Human cl rhFVIII
Enrollment 58
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Human-cl rhFVIII
Hide Arm/Group Description

The study consisted of 3 phases:

  1. Pharmacokinetic (PK) Phase: 58 previously treated (≥150 exposure days) immunocompetent adults with severe hemophilia A without inhibitors patients started and completed the PK phase (PK population). Patients were treated with single dose of FVIII (60±5 IU/kg). One patient discontinued after single PK administration.
  2. Prophylactic Treatment Phase I: 57 patients started and 56 completed Phase I; Patients were treated prophylactically every other day or 3x/week with a dose of 30-40 IU/kg BW for 1-3 months until PK data had been analysed.
  3. Prophylactic Treatment Phase II: 56 patients started and 52 completed Phase II. Patients were treated prophylactically for 6 months using the dose and dosing interval based on individual PK data.

All 58 patients were included in the safety (SAF) and the intention-to-treat (ITT) populations.
Period Title: Pharmacokinetic (PK) Evaluation Phase
Started 58
Completed 58
Not Completed 0
Period Title: Prophylactic Treatment Phase I
Started 57
Completed 56
Not Completed 1
Reason Not Completed
Lost to Follow-up             1
Period Title: Prophylactic Treatment Phase II
Started 56
Completed 52
Not Completed 4
Reason Not Completed
Lost to Follow-up             1
Withdrawn Consent             1
Did not attend completion visit             1
Discontinued medication             1
Arm/Group Title SAF/ITT Population
Hide Arm/Group Description All patients who received at least one infusion of Human-cI rhFVIII
Overall Number of Baseline Participants 58
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 58 participants
40.1  (13.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants
Female
0
   0.0%
Male
58
 100.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants
American Indian or Alaska Native
0
   0.0%
Asian
14
  24.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
3
   5.2%
White
39
  67.2%
More than one race
0
   0.0%
Unknown or Not Reported
2
   3.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 58 participants
Canada 4
Netherlands 2
United States 23
Japan 11
Finland 4
North Macedonia 4
Slovenia 2
France 6
Croatia 2
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 58 participants
77.0  (17.0)
Body mass index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 58 participants
25.7  (5.0)
Hemophilia Joint Health Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 58 participants
32.3  (20.2)
[1]
Measure Description: Joint health status will be assessed using the Hemophilia Joint Health Score (HJHS), which evaluates six index joints to produce a score between 0-124. Higher scores indicate worse joint health.
Blood group  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 58 participants
O
20
  34.5%
A
26
  44.8%
AB
1
   1.7%
B
7
  12.1%
Unknown/missing
4
   6.9%
1.Primary Outcome
Title Annualized Total Bleeding Rate of Individually Tailored Prophylaxis
Hide Description Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
Arm/Group Title Individualized Prophylaxis in GENA-21b GENA-01
Hide Arm/Group Description:
Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis
All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Overall Number of Participants Analyzed 56 22
Mean (Standard Deviation)
Unit of Measure: Bleeding events per year (ABR)
4.67  (6.46) 58.08  (30.78)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Individualized Prophylaxis in GENA-21b, GENA-01
Comments [Not Specified]
Type of Statistical Test Other
Comments Confirmative one-sided one-sample Poisson-test.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean ABR in patients with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial.
Method one-sided one-sample Poisson-test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR
Estimated Value 4.87
Confidence Interval (2-Sided) 95%
4.06 to 5.79
Estimation Comments A confidence interval of 97.5% for confirmative analysis was also used - the respective upper and lower limit CIs were 3.96-5.93
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Individualized Prophylaxis in GENA-21b, GENA-01
Comments [Not Specified]
Type of Statistical Test Other
Comments Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Negative Binomial regression model including a correction for overdispersion.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Negative binomial regression model
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 11.89
Confidence Interval (2-Sided) 95%
7.50 to 18.86
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Individualized Prophylaxis in GENA-21b, GENA-01
Comments [Not Specified]
Type of Statistical Test Other
Comments Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Poisson regression model including a correction for overdispersion.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Poisson regression model
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 10.14
Confidence Interval (2-Sided) 95%
6.12 to 16.80
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis
Hide Description Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
Arm/Group Title Individualised Prophylaxis in GENA-21b GENA-01
Hide Arm/Group Description:
Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis
All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Overall Number of Participants Analyzed 56 22
Mean (Standard Deviation)
Unit of Measure: Bleeding events per year (ABR)
2.98  (5.76) 38.46  (28.07)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Individualised Prophylaxis in GENA-21b, GENA-01
Comments [Not Specified]
Type of Statistical Test Other
Comments A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean spontaneous ABR in patients with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method One-sided one-sample Poisso
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR
Estimated Value 3.12
Confidence Interval (2-Sided) 95%
2.48 to 3.87
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis
Hide Description Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population comprised 29 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial at intervals of 2x/week or less. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
Arm/Group Title Prophylaxis 2x/Week or Less GENA-01
Hide Arm/Group Description:
Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis and were treated with a prophylaxis infusion frequency of 2x/week or less
All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01
Overall Number of Participants Analyzed 29 22
Mean (Standard Deviation)
Unit of Measure: Bleeding events per year (ABR)
4.82  (6.98) 58.08  (30.78)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Prophylaxis 2x/Week or Less, GENA-01
Comments [Not Specified]
Type of Statistical Test Other
Comments A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean ABR in patients with 2x/week prophylaxis or less with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method One-sided one-sample Poisson-test
Comments [Not Specified]
Method of Estimation Estimation Parameter ABR
Estimated Value 5.03
Confidence Interval (2-Sided) 95%
3.90 to 6.39
Estimation Comments A confidence interval of 97.5% for confirmative analysis was also used - the respective upper and lower limit CIs were 3.76-6.60
4.Secondary Outcome
Title Median Prophylactic Dosing Interval
Hide Description Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
Arm/Group Title Prophylaxis
Hide Arm/Group Description:
Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis
Overall Number of Participants Analyzed 56
Median (Inter-Quartile Range)
Unit of Measure: hours
83.9
(53.5 to 96.1)
5.Secondary Outcome
Title Mean Prophylactic Dosing Interval
Hide Description Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
Arm/Group Title Prophylaxis
Hide Arm/Group Description:
Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis
Overall Number of Participants Analyzed 56
Mean (Standard Deviation)
Unit of Measure: hours
83.0  (22.37)
6.Secondary Outcome
Title AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII
Hide Description AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay
Time Frame Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Hide Outcome Measure Data
Hide Analysis Population Description
The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
Arm/Group Title PK Evaluation
Hide Arm/Group Description:
PK-PP population
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: hr*IU/mL/(IU/kg)
0.302  (0.116)
7.Secondary Outcome
Title In-vivo Recovery (IVR) of Human-cl rhFVIII
Hide Description IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII
Time Frame Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Hide Outcome Measure Data
Hide Analysis Population Description
The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
Arm/Group Title PK Evaluation
Hide Arm/Group Description:
PK-PP population
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: % per IU/kg
1.775  (0.421)
8.Secondary Outcome
Title Half Life (t1/2) of Human-cl rhFVIII
Hide Description T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay
Time Frame Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Hide Outcome Measure Data
Hide Analysis Population Description
The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
Arm/Group Title PK Evaluation
Hide Arm/Group Description:
PK-PP population
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: hours
15.725  (4.029)
9.Secondary Outcome
Title Mean Residence Time (MRT) of Human-cl rhFVIII
Hide Description MRT of Human-cl rhFVIII measured using the one-stage (OS) assay
Time Frame Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Hide Outcome Measure Data
Hide Analysis Population Description
The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
Arm/Group Title PK Evaluation
Hide Arm/Group Description:
PK-PP population
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: hours
20.762  (5.997)
10.Secondary Outcome
Title Clearance (CL) of Human-cl rhFVIII
Hide Description CL of Human-cl rhFVIII measured using the one-stage (OS) assay
Time Frame Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Hide Outcome Measure Data
Hide Analysis Population Description
The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
Arm/Group Title PK Evaluation
Hide Arm/Group Description:
PK-PP population
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: mL/hr/kg
3.859  (1.670)
11.Secondary Outcome
Title Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII
Hide Description Vss of Human-cl rhFVIII measured using the one-stage (OS) assay
Time Frame Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
Hide Outcome Measure Data
Hide Analysis Population Description
The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
Arm/Group Title PK Evaluation
Hide Arm/Group Description:
PK-PP population
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: mL/kg
72.901  (16.454)
12.Secondary Outcome
Title Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)
Hide Description Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
Arm/Group Title Prophylaxis
Hide Arm/Group Description:
Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis in Phase III
Overall Number of Participants Analyzed 56
Mean (Standard Deviation)
Unit of Measure: IU/kg per week
83.7  (25.7)
13.Secondary Outcome
Title Number of Patients With Adverse Events (AEs)
Hide Description AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria
Time Frame At each study visit over the study duration (7-9 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial
Arm/Group Title SAF/ITT Population
Hide Arm/Group Description:
All patients who received at least one infusion of Human-cI rhFVIII
Overall Number of Participants Analyzed 58
Measure Type: Count of Participants
Unit of Measure: Participants
AE
34
  58.6%
No AE
24
  41.4%
Time Frame At each study visit over the study duration (7-9 months)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title SAF/ITT Population
Hide Arm/Group Description All patients who received at least one infusion of Human-cI rhFVIII
All-Cause Mortality
SAF/ITT Population
Affected / at Risk (%)
Total   0/58 (0.00%)    
Hide Serious Adverse Events
SAF/ITT Population
Affected / at Risk (%) # Events
Total   4/58 (6.90%)    
Blood and lymphatic system disorders   
Subdural haematoma †  1/58 (1.72%)  1
General disorders   
Pyrexia †  1/58 (1.72%)  1
Metabolism and nutrition disorders   
Hypokalemia †  1/58 (1.72%)  1
Musculoskeletal and connective tissue disorders   
Back pain †  1/58 (1.72%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Basosquamous carcinoma †  1/58 (1.72%)  1
Large B-cell lymphoma †  1/58 (1.72%)  1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
SAF/ITT Population
Affected / at Risk (%) # Events
Total   34/58 (58.62%)    
Blood and lymphatic system disorders   
Anemia †  2/58 (3.45%) 
Lymphadenopathy †  2/58 (3.45%) 
Gastrointestinal disorders   
Diarrhea †  3/58 (5.17%) 
Dyspepsia †  2/58 (3.45%) 
Gastritis †  2/58 (3.45%) 
General disorders   
Pyrexia †  4/58 (6.90%) 
Infections and infestations   
Nasopharyngitis †  12/58 (20.69%) 
Influenza †  3/58 (5.17%) 
Urinary tract infection †  3/58 (5.17%) 
Musculoskeletal and connective tissue disorders   
Arthralgia †  4/58 (6.90%) 
Bone pain †  2/58 (3.45%) 
Pain in extremity †  2/58 (3.45%) 
Nervous system disorders   
Headache †  5/58 (8.62%) 
Dizziness †  2/58 (3.45%) 
Psychiatric disorders   
Depression †  2/58 (3.45%) 
Insomnia †  2/58 (3.45%) 
Respiratory, thoracic and mediastinal disorders   
Oropharyngeal pain †  3/58 (5.17%) 
Nasal congestion †  2/58 (3.45%) 
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Octapharma agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Octapharma supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial. Octapharma also reserves the right to review data prior to publishing and provide comments/changes within a certain time period.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Sylvia Werner
Organization: Octapharma
Phone: 415 260-9577
EMail: sylvia.werner@octapharma.com
Layout table for additonal information
Responsible Party: Octapharma
ClinicalTrials.gov Identifier: NCT02256917    
Other Study ID Numbers: GENA-21B
First Submitted: September 30, 2014
First Posted: October 6, 2014
Results First Submitted: August 28, 2019
Results First Posted: December 3, 2019
Last Update Posted: January 19, 2021