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Early Prophylaxis Immunologic Challenge (EPIC) Study (EPIC)

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: NCT01376700
Recruitment Status : Terminated (It became unlikely to achieve the study objective of 50% reduction over published inhibitor rates. The Data Monitoring Committee supported this decision.)
First Posted : June 20, 2011
Results First Posted : October 9, 2014
Last Update Posted : February 27, 2019
Sponsor:
Collaborator:
Baxter Innovations GmbH
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Condition Hemophilia A
Intervention Biological: Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM)
Enrollment 22
Recruitment Details Enrollment was conducted in Europe and North America at 19 clinical sites.
Pre-assignment Details 22 participants were enrolled. One was a screen failure; one did not have screening laboratory assessments performed prior to study termination; and one met screening criteria, but was not exposed to investigational product prior to study termination. Therefore 19 participants were treated
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.
Period Title: Overall Study
Started 19
Completed 3
Not Completed 16
Reason Not Completed
Sponsor terminated study early             8
Low or high titer inhibitor             8
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.
Overall Number of Baseline Participants 19
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Weeks
Number Analyzed 19 participants
43.3  (10.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants
Female
0
   0.0%
Male
19
 100.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants
Serbia 1
United States 2
Czech Republic 2
Canada 1
Spain 1
Poland 4
Austria 1
Russian Federation 3
Bulgaria 1
Netherlands 1
Germany 2
1.Primary Outcome
Title Number of Participants With Severe and Moderately Severe Hemophilia A (FVIII ≤ 2%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE
Hide Description

Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing.

Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either:

  • i. High FVIII inhibitor titer (> 5 BU/mL) or
  • ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description

Safety Analysis Set

All study participants had severe Hemophilia A, less than 1% Factor VIII levels. (ie there were no moderately severe hemophilia A participants (FVIII levels >1% to ≤ 2%) in this study.

Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: participants
8
2.Secondary Outcome
Title Number of Participants With Severe Hemophilia A (FVIII ≤ 1%) With Factor VIII (FVIII) Inhibitor Formation Within the First 50 Exposure Days to ADVATE
Hide Description

Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing.

Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either:

  • i. High FVIII inhibitor titer (> 5 BU/mL) or
  • ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: participants
8
3.Secondary Outcome
Title Number of Exposure Days of Treatment With Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment
Hide Description

Confirmed inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 BU/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either:

  • i. High FVIII inhibitor titer (> 5 BU/mL) or
  • ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Median (Inter-Quartile Range)
Unit of Measure: days
14.5
(7.0 to 21.0)
4.Secondary Outcome
Title Number of Participants With Low-titer, High-titer, Transient, and All Factor VIII (FVIII) Inhibitors
Hide Description
  • High FVIII inhibitor titer (> 5 Bethesda Unit (BU)/mL)
  • Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL)
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: participants
Low FVIII inhibitor titer 5
High FVIII inhibitor titer 3
All FVIII inhibitors 8
5.Secondary Outcome
Title Number, Type, and Severity of All Bleeds Experienced When Different Prophylactic Dosing Frequencies Are Used (Once or Twice Per Week and Unknown Frequency)
Hide Description

Nominal Dosing Frequency:

  • 1 time per week
  • 2 times per week
  • Unknown dosing frequency (UK)

Bleeding Type (BT):

  • Skin
  • Muscle and Soft Tissue
  • Mucosal
  • Joint
  • Other
  • Multiple
  • Total

Bleeding severity:

  • Minor
  • Moderate
  • Severe
  • Total
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeds
193
Measure Type: Number
Unit of Measure: Bleeds
Dose: 1/week; Skin; Minor Bleed 130
Dose: 1/week; Skin; Moderate Bleed 2
Dose: 1/week; Skin; Severe Bleed 0
Dose: 1/week; Skin; Total Bleeds 132
Dose: 1/week; Muscle & Soft Tissue; Minor Bleed 8
Dose: 1/week; Muscle & Soft Tissue; Moderate Bleed 10
Dose: 1/week; Muscle & Soft Tissue; Severe Bleed 0
Dose: 1/week; Muscle & Soft Tissue; Total Bleeds 18
Dose: 1/week; Mucosal; Minor Bleed 9
Dose: 1/week; Mucosal; Moderate Bleed 3
Dose: 1/week; Mucosal; Severe Bleed 0
Dose: 1/week; Mucosal; Total Bleeds 12
Dose: 1/week; Joint; Minor Bleed 0
Dose: 1/week; Joint; Moderate Bleed 0
Dose: 1/week; Joint; Severe Bleed 0
Dose: 1/week; Joint; Total Bleeds 0
Dose: 1/week; Other BT; Minor Bleed 3
Dose: 1/week; Other BT; Moderate Bleed 3
Dose: 1/week; Other BT; Severe Bleed 1
Dose: 1/week; Other BT; Total Bleeds 7
Dose: 1/week; Multiple BT; Minor Bleed 2
Dose: 1/week; Multiple BT; Moderate Bleed 1
Dose: 1/week; Multiple BT; Severe Bleed 0
Dose: 1/week; Multiple BT; Total Bleeds 3
Dose: 1/week; Total BT; Minor Bleed 152
Dose: 1/week; Total BT; Moderate Bleed 19
Dose: 1/week; Total BT; Severe Bleed 1
Dose: 1/week; Total BT; Total Bleeds 172
Dose: 2/week; Skin; Minor Bleed 9
Dose: 2/week; Skin; Moderate Bleed 0
Dose: 2/week; Skin; Severe Bleed 0
Dose: 2/week; Skin; Total Bleeds 9
Dose: 2/week; Muscle & Soft Tissue; Minor Bleed 0
Dose: 2/week; Muscle & Soft Tissue; Moderate Bleed 1
Dose: 2/week; Muscle & Soft Tissue; Severe Bleed 0
Dose: 2/week; Muscle & Soft Tissue; Total Bleeds 1
Dose: 2/week; Mucosal; Minor Bleed 3
Dose: 2/week; Mucosal; Moderate Bleed 1
Dose: 2/week; Mucosal; Severe Bleed 0
Dose: 2/week; Mucosal; Total Bleeds 4
Dose: 2/week; Joint; Minor Bleed 0
Dose: 2/week; Joint; Moderate Bleed 0
Dose: 2/week; Joint; Severe Bleed 0
Dose: 2/week; Joint; Total Bleeds 0
Dose: 2/week; Other BT; Minor Bleed 0
Dose: 2/week; Other BT; Moderate Bleed 0
Dose: 2/week; Other BT; Severe Bleed 0
Dose: 2/week; Other BT; Total Bleeds 0
Dose: 2/week; Multiple BT; Minor Bleed 0
Dose: 2/week; Multiple BT; Moderate Bleed 0
Dose: 2/week; Multiple BT; Severe Bleed 0
Dose: 2/week; Multiple BT; Total Bleeds 0
Dose: 2/week; Total BT; Minor Bleed 12
Dose: 2/week; Total BT; Moderate Bleed 2
Dose: 2/week; Total BT; Severe Bleed 0
Dose: 2/week; Total BT; Total Bleeds 14
Dose: UK/week; Skin; Minor Bleed 4
Dose: UK/week; Skin; Moderate Bleed 1
Dose: UK/week; Skin; Severe Bleed 0
Dose: UK/week; Skin; Total Bleeds 5
Dose: UK/week; Muscle & Soft Tissue; Minor Bleed 0
Dose: UK/week; Muscle & Soft Tissue;Moderate Bleed 1
Dose: UK/week; Muscle & Soft Tissue; Severe Bleed 0
Dose: UK/week; Muscle & Soft Tissue; Total Bleeds 1
Dose: UK/week; Mucosal; Minor Bleed 0
Dose: UK/week; Mucosal; Moderate Bleed 0
Dose: UK/week; Mucosal; Severe Bleed 0
Dose: UK/week; Mucosal; Total Bleeds 0
Dose: UK/week; Joint; Minor Bleed 0
Dose: UK/week; Joint; Moderate Bleed 1
Dose: UK/week; Joint; Severe Bleed 0
Dose: UK/week; Joint; Total Bleeds 1
Dose: UK/week; Other BT; Minor Bleed 0
Dose: UK/week; Other BT; Moderate Bleed 0
Dose: UK/week; Other BT; Severe Bleed 0
Dose: UK/week; Other BT; Total Bleeds 0
Dose: UK/week; Multiple BT; Minor Bleed 0
Dose: UK/week; Multiple BT; Moderate Bleed 0
Dose: UK /week; Multiple BT; Severe Bleed 0
Dose: UK /week; Multiple BT; Total Bleeds 0
Dose: UK /week; Total BT; Minor Bleed 4
Dose: UK /week; Total BT; Moderate Bleed 3
Dose: UK /week; Total BT; Severe Bleed 0
Dose: UK /week; Total BT; Total Bleeds 7
6.Secondary Outcome
Title Number and Type of Surgeries
Hide Description
  • Elective surgery is not allowed during period of first 20 exposure days (EDs)
  • Peripherally inserted central catheter (PICC)
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: surgeries
Surgery: Cimino Shunt 1
Surgery: PICC Line Insertion in right arm 1
7.Secondary Outcome
Title Correlation of Known Risk Factors to Factor VIII (FVIII) Inhibitor Formation
Hide Description [Not Specified]
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the low number of subjects available for evaluation, no statistical tests were performed to assess associations between known risk factors to inhibitor formation.
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
8.Secondary Outcome
Title Total Factor VIII (FVIII) Consumption by Participant
Hide Description [Not Specified]
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the low number of subjects available for evaluation, no statistical tests were performed to assess the total FVIII consumption by participant
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
9.Secondary Outcome
Title FVIII-Specific Antibody Isotype for All Participants at Study Entry and Every 10 Exposure Days (EDs)
Hide Description [Not Specified]
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Summary statistics of FVIII-Specific Antibody Isotypes were not performed due to the early termination of the study
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
10.Secondary Outcome
Title Number of Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) at Least Possibly Related to ADVATE
Hide Description Possibly or probably related adverse events
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: adverse events
SAEs 9
non-SAEs 1
11.Post-Hoc Outcome
Title Number of Participants With Factor VIII (FVIII) Inhibitors by Inhibitor Type (Only ‘True’ Inhibitors)
Hide Description

’True’ positive inhibitor (PI) defined as any FVIII inhibitor assay result ≥0.6 Bethesda Units (BU)/mL confirmed by central lab on 2 consecutive samples, ie ≥2 PI results (including first PI test, in accordance with study protocol) assessed as either:

i. High FVIII inhibitor titer (> 5 BU/mL)

ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL). In addition, to be classified as ‘true’ positive low FVIII inhibitors titer (≥0.6 - ≤5.0 BU/mL), one of following criteria must be met:

  • a) Lower or absent therapeutic response at infusion of standard replacement doses (“clinically relevant”) as deemed by the clinician in charge.
  • b) Any lab result of binding FVIII antibodies (IgM, IgA, IgG, IgG1, IgG2, IgG3, or IgG4) must be positive.

Classification based on first positive FVIII inhibitor assessment. Inhibitor test result is:

  • > 5 BU/mL, then categorized as a high-titer inhibitor
  • ≥0.6 BU/mL but ≤5 BU/mL, then categorized as a low-titer.
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description:
Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.
Overall Number of Participants Analyzed 19
Measure Type: Number
Unit of Measure: participants
Inhibitor Type: Low-Titer 3
Inhibitor Type: High-Titer 3
Inhibitor Type: All Inhibitors 6
12.Post-Hoc Outcome
Title Number of Inhibitors in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) - (Only ‘True’ Inhibitors)
Hide Description

PUPs = no previous FVIII exposure; MTPs ≤4 previous FVIII exposures

’True’ positive inhibitor (PI) = any FVIII inhibitor assay result ≥0.6 Bethesda Units (BU)/mL confirmed by central lab on 2 consecutive samples, ie ≥2 PI results (including first PI test, per study protocol) assessed as either:

i. High FVIII inhibitor titer (>5 BU/mL)

ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL). In addition, to be classified as ‘true’ positive low FVIII inhibitors titer (≥0.6 - ≤5.0 BU/mL), one of following criteria must be met:

  • a) Lower or absent therapeutic response at infusion of standard replacement doses (“clinically relevant”) as deemed by clinician in charge.
  • b) Any lab result of binding FVIII antibodies (IgM, IgA, IgG, IgG1, IgG2, IgG3, or IgG4) must be positive.

Classification based on first positive FVIII inhibitor assessment. Inhibitor test result is:

  • > 5 BU/mL, categorized as high-titer inhibitor
  • ≥0.6 BU/mL but ≤5 BU/mL, categorized as low-titer
Time Frame 50 exposure days to ADVATE
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set
Arm/Group Title PUPs MTPs
Hide Arm/Group Description:
No previous FVIII exposure
≤4 previous FVIII exposures
Overall Number of Participants Analyzed 11 8
Measure Type: Number
Unit of Measure: inhibitors
3 3
Time Frame 1 year and 3 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title ADVATE - Prophylactic Regimen
Hide Arm/Group Description

Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter.

Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

All-Cause Mortality
ADVATE - Prophylactic Regimen
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
ADVATE - Prophylactic Regimen
Affected / at Risk (%) # Events
Total   11/19 (57.89%)    
Blood and lymphatic system disorders   
FACTOR VIII INHIBITION  8/19 (42.11%)  8
Injury, poisoning and procedural complications   
HEAD INJURY  1/19 (5.26%)  1
TRAUMATIC HAEMATOMA  1/19 (5.26%)  2
Musculoskeletal and connective tissue disorders   
SOFT TISSUE HAEMORRHAGE  1/19 (5.26%)  1
Surgical and medical procedures   
ARTERIOVENOUS FISTULA OPERATION  1/19 (5.26%)  1
Vascular disorders   
HAEMORRHAGE  2/19 (10.53%)  2
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%
ADVATE - Prophylactic Regimen
Affected / at Risk (%) # Events
Total   19/19 (100.00%)    
Blood and lymphatic system disorders   
FACTOR VIII INHIBITION (UNCONFIRMED)  1/19 (5.26%)  1
LYMPHADENOPATHY  1/19 (5.26%)  1
Ear and labyrinth disorders   
MIDDLE EAR EFFUSION  1/19 (5.26%)  1
Eye disorders   
EYE DISCHARGE  1/19 (5.26%)  1
LACRIMATION INCREASED  1/19 (5.26%)  1
Gastrointestinal disorders   
CONSTIPATION  1/19 (5.26%)  1
DIARRHOEA  3/19 (15.79%)  3
TEETHING  4/19 (21.05%)  10
VOMITING  5/19 (26.32%)  6
General disorders   
PYREXIA  10/19 (52.63%)  13
Immune system disorders   
FOOD ALLERGY  1/19 (5.26%)  1
Infections and infestations   
ACUTE TONSILLITIS  1/19 (5.26%)  2
BRONCHITIS  1/19 (5.26%)  2
CANDIDIASIS  1/19 (5.26%)  1
COXSACKIE VIRAL INFECTION  1/19 (5.26%)  1
EAR INFECTION  2/19 (10.53%)  2
GASTROENTERITIS  1/19 (5.26%)  2
GASTROENTERITIS VIRAL  1/19 (5.26%)  1
HORDEOLUM  1/19 (5.26%)  1
NASOPHARYNGITIS  6/19 (31.58%)  7
RESPIRATORY TRACT INFECTION  1/19 (5.26%)  1
RHINITIS  8/19 (42.11%)  13
TONSILLITIS  1/19 (5.26%)  1
UPPER RESPIRATORY TRACT INFECTION  3/19 (15.79%)  7
VIRAL INFECTION  1/19 (5.26%)  1
Injury, poisoning and procedural complications   
FACE INJURY  1/19 (5.26%)  1
FALL  1/19 (5.26%)  1
LIP INJURY  1/19 (5.26%)  2
TONGUE INJURY  1/19 (5.26%)  1
VACCINATION COMPLICATION  1/19 (5.26%)  1
WRONG DRUG ADMINISTERED  1/19 (5.26%)  3
Metabolism and nutrition disorders   
VITAMIN D DEFICIENCY  1/19 (5.26%)  1
Musculoskeletal and connective tissue disorders   
JOINT RANGE OF MOTION DECREASED  1/19 (5.26%)  1
Respiratory, thoracic and mediastinal disorders   
COUGH  6/19 (31.58%)  6
NASAL CONGESTION  1/19 (5.26%)  1
NASAL DRYNESS  1/19 (5.26%)  2
OROPHARYNGEAL PAIN  1/19 (5.26%)  1
RHINORRHOEA  2/19 (10.53%)  3
Skin and subcutaneous tissue disorders   
DERMATITIS  1/19 (5.26%)  1
DERMATITIS ALLERGIC  1/19 (5.26%)  1
DERMATITIS DIAPER  1/19 (5.26%)  5
ECZEMA  1/19 (5.26%)  1
ERYTHEMA  1/19 (5.26%)  1
RASH  3/19 (15.79%)  3
Vascular disorders   
HAEMATOMA  1/19 (5.26%)  1
VASCULAR RUPTURE  1/19 (5.26%)  1
1
Term from vocabulary, MedDRA (Unspecified)

Early termination lead to:

  • No statistical tests done on risk factors & inhibitor formation.
  • FVIII consumption by participant not calculated due to large variation in # of EDs.
  • FVIII-Specific Antibody Isotypes summary statistics not done.
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.
Agreements may vary with individual PIs, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication or up to 2 years after study completion. Baxter requires a review of results communications (eg for confidential information) ≥30 days prior to submission/communication. Baxter may request additional delay of ≤6 months (e.g., for intellectual property protection). Prior authorization may be required
Results Point of Contact
Name/Title: Study Director
Organization: Shire
Phone: +1 866 842 5335
Responsible Party: Shire ( Baxalta now part of Shire )
ClinicalTrials.gov Identifier: NCT01376700     History of Changes
Other Study ID Numbers: 061002
2011-000410-18 ( EudraCT Number )
First Submitted: June 17, 2011
First Posted: June 20, 2011
Results First Submitted: September 17, 2014
Results First Posted: October 9, 2014
Last Update Posted: February 27, 2019