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Efficacy and Safety Study of a Recombinant Protein-Free Manufactured Factor VIII (rAHF-PFM) in Previously Untreated Hemophilia A Patients

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ClinicalTrials.gov Identifier: NCT00157157
Recruitment Status : Completed
First Posted : September 12, 2005
Results First Posted : July 15, 2011
Last Update Posted : May 21, 2019
Sponsor:
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia A
Intervention Biological: Recombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM)
Enrollment 66
Recruitment Details Recruitment was conducted in the U.S., Canada, and Europe at 24 study sites.
Pre-assignment Details Participants screened for maximum 21 days. Study was not randomized; it was an open-label evaluation. Prior to initial infusion, a minimum washout period of 3 days was required. 11 participants who enrolled did not receive any rAHF-PFM infusions (3 withdrew consent, 6 screen failures, 1 non-compliance with screening, 1 pre-existing low hemoglobin)
Arm/Group Title Previously Untreated Patients (PUPs)
Hide Arm/Group Description rAHF-PFM was dosed according to a therapeutic regimen which was determined by the investigator (ie: standard regimen [25 to 50 IU/kg body weight, 3 to 4 times per week]; a modified prophylactic regimen [dose and frequency selected by investigator] or on–demand treatment [dose selected by investigator]). The dosing regimen used to treat bleeding episodes (BEs) was at the discretion of the investigator and in accordance with the institution’s standard of care for the type of bleeding episodes diagnosed.
Period Title: Overall Study
Started 55
Completed 44
Not Completed 11
Reason Not Completed
Withdrawal by Subject             6
Physician Decision             1
Lost to Follow-up             1
Enrolled in another study             1
Met exclusion criteria             1
Inclusion not met- baseline FVIII value             1
Arm/Group Title PUPs
Hide Arm/Group Description [Not Specified]
Overall Number of Baseline Participants 55
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 55 participants
<6 months 21
6-12 months 26
≥13 months 8
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 55 participants
Female
0
   0.0%
Male
55
 100.0%
1.Primary Outcome
Title Factor VIII Inhibitor Development
Hide Description Percentage of treated participants who developed factor VIII inhibitors
Time Frame Assessed during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 infusion of rAHF-PFM
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage
29.1
(17.1 to 41.1)
2.Secondary Outcome
Title Bleeding Episodes Treated With 1 to ≥4 Infusions
Hide Description The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis
Time Frame Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 infusion of rAHF-PFM for the treatment of bleeding episodes
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 44
Measure Type: Number
Unit of Measure: Bleeding episodes
1 infusion 356
2 infusions 107
3 infusions 35
4 or more infusions 19
3.Secondary Outcome
Title Assessment of Hemostasis for Treatment of Bleeding Episodes
Hide Description

Number of rAHF-PFM-treated bleeding episodes with treater assessment of hemostasis (4-point ordinal scale):

Excellent: Full pain relief & bleeding cessation within ~8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis;

Good: Definite pain relief and/or improvement in bleeding within ~8 hrs after infusion. Possibly requires >1 infusion for complete resolution;

Fair: Probable or slight relief of pain & slight improvement in bleeding within ~8 hrs after infusion. Requires >1 infusion for complete resolution; or

None: No improvement or condition worsens.

Time Frame Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 infusion of rAHF-PFM and had at least 1 treated bleeding episode. The 1 rating of "none" was for the first 2 infusions, the last infusion was rated as "good".
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 44
Measure Type: Number
Unit of Measure: bleeding episodes
Excellent 258
Good 177
Fair 30
None 1
Unknown/not assessed 51
4.Secondary Outcome
Title Annualized Rate of Bleeding Episodes
Hide Description Number of bleeding episodes per subject annualized over 1 year for all etiologies
Time Frame Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants treated for at least 3 months with investigator-defined on-demand treatment (for dose) or prophylaxis (for dose and infusion frequency) for >80% of the treatment period
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 43
Median (Full Range)
Unit of Measure: bleeding episodes per subject per year
4.95
(1.01 to 32.70)
5.Secondary Outcome
Title Weekly rAHF-PFM Utilization
Hide Description

Weight-Adjusted Weekly Dose for Prophylaxis, On-Demand Treatment, and Perioperative Management.

rAHF-PFM dose determined by the investigator (ie: standard regimen [25-50 IU/kg body weight, 3-4 times per week]; modified prophylactic regimen [dose and frequency selected by investigator] or on–demand treatment [dose selected by investigator]). Dosing to treat BEs was at investigator's discretion and in accordance with institution’s standard of care.

rAHF-PFM was administered I.V. via bolus infusion, except for perioperative management when it was given either by continuous or bolus infusion.

Time Frame Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants treated for at least 3 months with investigator-defined on-demand treatment (for dose) or prophylaxis (for dose and infusion frequency) for >80% of the treatment period
Arm/Group Title PUPs -During Prophylaxis PUPs -During On-Demand Treatment PUPs -During Perioperative Management
Hide Arm/Group Description:
rAHF-PFM was dosed according to a therapeutic regimen which was determined by the investigator (ie: standard regimen [25 to 50 IU/kg body weight, 3 to 4 times per week]; a modified prophylactic regimen [dose and frequency selected by investigator]. The dosing regimen used to treat BEs was at the discretion of the investigator and in accordance with the institution’s standard of care for the type of bleeding episode (BE) diagnosed.
The dosing regimen used to treat BEs was at the discretion of the investigator and in accordance with the institution’s standard of care for the type of BE diagnosed.
rAHF-PFM was administered intravenously via bolus infusion, or continuous infusion. The dosing regimen used was at the discretion of the investigator and in accordance with the institution’s standard of care.
Overall Number of Participants Analyzed 36 47 25
Median (Full Range)
Unit of Measure: IU/kg
87.1
(6.5 to 352.3)
12.5
(2.4 to 176.8)
606.4
(256.5 to 1951.0)
6.Secondary Outcome
Title In Vivo Incremental Recovery
Hide Description Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits.
Time Frame 30 minutes pre-infusion to 30 minutes post-infusion
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received pharmacokinetic rAHF-PFM infusions, did not develop inhibitors, and had assessments
Arm/Group Title PUPs -Initial Visit PUPs -Termination Visit
Hide Arm/Group Description:
Incremental recovery at the Initial Study Visit
Incremental recovery at the Termination Study Visit
Overall Number of Participants Analyzed 4 12
Median (Full Range)
Unit of Measure: IU/dL per IU/kg
1.81
(0.74 to 1.92)
1.71
(1.32 to 2.11)
7.Secondary Outcome
Title Assessment of Intra-operative Hemostasis
Hide Description

Number of surgical procedures managed with rAHF-PFM and with surgeon's assessment of hemostasis based on a 4-point ordinal scale:

Excellent: ≤ average predicted blood loss for matched procedures in healthy individuals

Good: > average predicted blood loss, but ≤ maximal predicted blood loss for matched procedures in healthy individuals

Fair: > maximal predicted blood loss for matched procedures in healthy individuals, and hemostasis was achieved

None: uncontrolled hemostasis with proper dosing, necessitating a change in treatment regimen

Time Frame Assessed at the time of discharge from recovery room
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants who underwent a surgical procedure with an intraoperative assessment of hemostatic efficacy
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 22
Measure Type: Number
Unit of Measure: Procedures
Excellent 18
Good 4
Not Applicable 0
Not Done 0
8.Secondary Outcome
Title Assessment of Postoperative Hemostasis
Hide Description

Number of surgical procedures managed with rAHF-PFM and with investigator's assessment of hemostasis based on a 4-point ordinal scale:

Excellent: hemostasis was as good as or better than other licensed factor VIII products for matched procedure

Good: hemostasis was probably as good as other licensed factor VIII products for matched procedure

Fair: hemostasis was clearly < optimal for matched procedure, without need to change regimen

None: bleeding from inadequate response with proper dosing, necessitating a change in regimen

Time Frame Assessed at the time of discharge from hospital or clinic
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants who underwent a surgical procedure with a postoperative assessment of hemostatic efficacy
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 27
Measure Type: Number
Unit of Measure: Procedures
Excellent 23
Good 2
Not Applicable 1
Not Done 1
9.Secondary Outcome
Title Assessment of Blood Loss During Surgical Procedures
Hide Description Percentage of actual intraoperative blood loss compared to preoperatively predicted average and maximal blood loss in hemostatically normal matched individuals (from institutional blood bank records)
Time Frame Predicted volumes preoperatively estimated and actual volumes intraoperatively recorded
Hide Outcome Measure Data
Hide Analysis Population Description
Number of participants who underwent a surgical procedure with blood loss assessments
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 27
Median (Full Range)
Unit of Measure: Percentage Blood Loss
Blood loss as percentage of predicted average
50.0
(0.0 to 250)
Blood loss as percentage of predicted maximal
20.0
(0.0 to 100.0)
10.Secondary Outcome
Title Adverse Events Deemed Related to Treatment
Hide Description Percentage of participants who reported AEs deemed related to treatment with rAHF-PFM
Time Frame Reported during the study period which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 infusion of rAHF-PFM
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 55
Measure Type: Number
Unit of Measure: Percentage of Participants
36.4
11.Secondary Outcome
Title Development of Antibodies to Heterologous Proteins
Hide Description Percentage of treated participants who developed antibodies to heterologous proteins (ie, Chinese Hamster Ovary Cell Protein, Murine IgG, or Recombinant Human VWF)
Time Frame Assessed at baseline, throughout the duration of the study, which was to be at least 75 exposure days or 3 years (whichever came first), and at the termination visit.
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least 1 infusion of rAHF-PFM and had assessments of heterologous antibodies
Arm/Group Title PUPs
Hide Arm/Group Description:
[Not Specified]
Overall Number of Participants Analyzed 55
Measure Type: Number
Unit of Measure: Percentage of Participants
Antibodies to Chinese Hamster Ovary Cell Protein 0.00
Antibodies to Murine IgG 0.00
Antibodies to Recombinant Human VWF (n=54) 0.00
12.Post-Hoc Outcome
Title Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors
Hide Description Number of treated participants who developed an inhibitor
Time Frame Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Immunogenicity Analysis Set- Participants who developed an inhibitor or who were inhibitor-free with ≥10 exposure days to rAHF-PFM
Arm/Group Title PUPs - Did Not Develop Factor VIII Inhibitor PUPs - Developed Factor VIII Inhibitor
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 34 16
Measure Type: Number
Unit of Measure: Participants
Has Family History of Inhibitors 6 8
Unknown Family History of Inhibitors 2 1
No Family History of Inhibitors 26 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PUPs - Did Not Develop Factor VIII Inhibitor, PUPs - Developed Factor VIII Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.95
Confidence Interval 95%
1.29 to 19.06
Estimation Comments [Not Specified]
13.Post-Hoc Outcome
Title Factor VIII Inhibitor Risk Factor: Race
Hide Description Number of treated participants who developed an inhibitor
Time Frame Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Immunogenicity Analysis Set- Participants who developed an inhibitor or who were inhibitor-free with ≥10 exposure days to rAHF-PFM
Arm/Group Title PUPs - Did Not Develop Factor VIII Inhibitor PUPs - Developed Factor VIII Inhibitor
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 34 16
Measure Type: Number
Unit of Measure: Participants
Non-Caucasian 8 9
Caucasian 26 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PUPs - Did Not Develop Factor VIII Inhibitor, PUPs - Developed Factor VIII Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.18
Confidence Interval 95%
1.18 to 14.82
Estimation Comments [Not Specified]
14.Post-Hoc Outcome
Title Factor VIII Inhibitor Risk Factor: Number of Participants With Intensive Treatment and High Dose (≤20 Exposure Days (EDs))
Hide Description Immunogenicity Analysis Set- Participants with 5 consecutive study days of a mean infusion dose of FVIII >50 IU/kg within ≤20 EDs who developed an inhibitor
Time Frame Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
Hide Outcome Measure Data
Hide Analysis Population Description
Immunogenicity Analysis Set- Participants who developed an inhibitor or who were inhibitor-free with ≥10 exposure days to rAHF-PFM
Arm/Group Title PUPs - Did Not Develop Factor VIII Inhibitor PUPs - Developed Factor VIII Inhibitor
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 34 16
Measure Type: Number
Unit of Measure: Participants
Received intensive treatment & high dose 4 6
No intensive treatment & high dose 30 10
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PUPs - Did Not Develop Factor VIII Inhibitor, PUPs - Developed Factor VIII Inhibitor
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 4.50
Confidence Interval 95%
1.05 to 19.25
Estimation Comments [Not Specified]
Time Frame Study period was to be at least 75 exposure days or 3 years (whichever came first)
Adverse Event Reporting Description Median days on study was 498 (range: 82 to 1360) days. Median days of rAHF-PFM exposure was 76 (range: 1 to 414) exposure days.
 
Arm/Group Title PUPs
Hide Arm/Group Description [Not Specified]
All-Cause Mortality
PUPs
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
PUPs
Affected / at Risk (%) # Events
Total   28/55 (50.91%)    
Blood and lymphatic system disorders   
Factor VIII inhibition  16/55 (29.09%)  16
Coagulopathy  2/55 (3.64%)  3
General disorders   
Pyrexia  2/55 (3.64%)  2
Catheter site haematoma  1/55 (1.82%)  1
Infections and infestations   
Bacteraemia  1/55 (1.82%)  1
Bronchitis  1/55 (1.82%)  1
Catheter bacteraemia  1/55 (1.82%)  1
Catheter related infection  1/55 (1.82%)  3
Pneumonia  1/55 (1.82%)  1
Respiratory syncytial virus infection  1/55 (1.82%)  1
Injury, poisoning and procedural complications   
Mouth injury  2/55 (3.64%)  2
Contusion  1/55 (1.82%)  1
Head injury  1/55 (1.82%)  1
Skin laceration  1/55 (1.82%)  1
Tongue injury  1/55 (1.82%)  1
Metabolism and nutrition disorders   
Dehydration  1/55 (1.82%)  1
Musculoskeletal and connective tissue disorders   
Haemarthrosis  1/55 (1.82%)  1
Respiratory, thoracic and mediastinal disorders   
Bronchial hyperreactivity  1/55 (1.82%)  3
Cough  1/55 (1.82%)  2
Wheezing  1/55 (1.82%)  2
Vascular disorders   
Haematoma  1/55 (1.82%)  1
1
Term from vocabulary, MedDRA (Unspecified)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
PUPs
Affected / at Risk (%) # Events
Total   52/55 (94.55%)    
Blood and lymphatic system disorders   
Anaemia  10/55 (18.18%)  13
Iron deficiency anaemia  5/55 (9.09%)  8
Ear and labyrinth disorders   
Ear pain  3/55 (5.45%)  3
Eye disorders   
Conjuctivitis  9/55 (16.36%)  12
Gastrointestinal disorders   
Diarrhea  20/55 (36.36%)  31
Vomiting  17/55 (30.91%)  29
Abdominal pain  3/55 (5.45%)  5
General disorders   
Pyrexia  39/55 (70.91%)  137
Pain  4/55 (7.27%)  6
Infections and infestations   
Nasopharyngitis  28/55 (50.91%)  80
Ear infection  20/55 (36.36%)  44
Upper respiratory tract infection  16/55 (29.09%)  35
Otitis media  7/55 (12.73%)  13
Hand-foot-and-mouth disease  5/55 (9.09%)  5
Bronchitis  4/55 (7.27%)  10
Influenza  4/55 (7.27%)  8
Pharyngitis  4/55 (7.27%)  4
Rhinitis  4/55 (7.27%)  14
Varicella  4/55 (7.27%)  4
Croup infectious  3/55 (5.45%)  3
Gasteroenteritis  3/55 (5.45%)  3
Viral infection  3/55 (5.45%)  5
Injury, poisoning and procedural complications   
Procedural pain  9/55 (16.36%)  11
Arthropod bite  4/55 (7.27%)  5
Mouth injury  3/55 (5.45%)  4
Skin laceration  3/55 (5.45%)  3
Musculoskeletal and connective tissue disorders   
Arthralgia  3/55 (5.45%)  4
Respiratory, thoracic and mediastinal disorders   
Cough  23/55 (41.82%)  65
Rhinorrhoea  22/55 (40.00%)  54
Nasal congestion  15/55 (27.27%)  48
Wheezing  6/55 (10.91%)  10
Oropharyngeal pain  3/55 (5.45%)  4
Skin and subcutaneous tissue disorders   
Rash  13/55 (23.64%)  18
Dermatitis diaper  7/55 (12.73%)  8
Urticaria  5/55 (9.09%)  5
1
Term from vocabulary, MedDRA (Unspecified)
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.
Baxter's agreements with PIs vary per individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication or 1 year after study completion. Baxter requires a review of results communications (e.g., for confidential information) 30 days prior to submission or communication. Baxter may request an additional delay of up to 90 days (e.g., to allow for intellectual property protection).
Results Point of Contact
Name/Title: Study Director
Organization: Shire
Phone: +1 866 842 5335
Publications of Results:
Ewenstein B., Patrone L, Schroth P, Spotts G, Fritsch S, Pavlova B, Ehrlich H. Efficacy of antihemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM) in bleed prevention. J Thromb Haemost. 2007; 5(Suppl 2): P-S-179.
Ewenstein B., Patrone L, Schroth P, Spotts G, Fritsch S, Pavlova B, Ehrlich H. Efficacy of antihemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM) in bleed treatment. J Thromb Haemost. 2007; 5(Suppl 2)v: P-S-180.
Responsible Party: Shire ( Baxalta now part of Shire )
ClinicalTrials.gov Identifier: NCT00157157     History of Changes
Other Study ID Numbers: 060103
First Submitted: September 9, 2005
First Posted: September 12, 2005
Results First Submitted: February 15, 2011
Results First Posted: July 15, 2011
Last Update Posted: May 21, 2019