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Recombinant Factor VIIa BI (rFVIIa BI) Treatment of Acute Bleeding Episodes Per an On-demand Regimen

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ClinicalTrials.gov Identifier: NCT01757405
Recruitment Status : Completed
First Posted : December 28, 2012
Results First Posted : October 25, 2016
Last Update Posted : October 23, 2017
Sponsor:
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Hemophilia A
Hemophilia B
Intervention Biological: Recombinant Factor VIIa BI (rFVIIa BI)
Enrollment 40
Recruitment Details Enrollment was conduced at 16 clinical sites from the following countries: Japan, Taiwan, Poland, Romania, Russian Federation, Serbia, Spain, Ukraine and the United States.
Pre-assignment Details 40 participants provided informed consent and were screened for study participation, of which there was 1 screen failure. 39 participants (in pre-assignment period) were randomized where 1 participant withdrew after randomization but prior to treatment, therefore 38 participants were treated with recombinant activated factor VII BI (rFVIIa).
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions. Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Period Title: Overall Study
Started 18 20
Completed 17 18
Not Completed 1 2
Reason Not Completed
Lost to Follow-up             1             1
Withdrawal by Subject             0             1
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI Total
Hide Arm/Group Description Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions. Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion. Total of all reporting groups
Overall Number of Baseline Participants 18 20 38
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 18 participants 20 participants 38 participants
28
(12 to 53)
28
(12 to 54)
28
(12 to 54)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 20 participants 38 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
18
 100.0%
20
 100.0%
38
 100.0%
1.Primary Outcome
Title Percentage of Bleeding Episode With "Treatment Success"
Hide Description No additional hemostatic product required within 12 hours of first dose other than the prescribed dosing regimen.
Time Frame within 12 hours of first dose
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Dataset
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description:
Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions.
Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Overall Number of Participants Analyzed 18 20
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes
289 256
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent of bleeding episodes
96.19
(93.31 to 97.86)
79.30
(73.92 to 83.81)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI, Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Comments

Equivalence test of successfully treated bleeding episodes (BEs) between or within treatment arms.

Denoting the success rates in the two treatment groups by p1 and p2 , the null hypotheses of H01 :

p1/p2 < 0.83 and H02 : p1/p2 > 1.20 was implicitly tested against the one-sided alternatives Ha1: 0.83 ≤ p1/p2 and Ha2 : p1/p2 ≤ 1.20, by comparing the 90% two-sided confidence interval (CI) of the ratio of success proportions to the equivalence region defined as [0.83, 1.20].

Type of Statistical Test Non-Inferiority or Equivalence
Comments Equivalence of treatment success proportions in all bleeding episodes for the two treatment groups was determined by comparing the 90% two-sided CI of the ratio of success proportions to the equivalence region defined as [0.83, 1.20].
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Ratio of success proportion
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of success proportion
Estimated Value 1.21
Confidence Interval (2-Sided) 90%
1.15 to 1.28
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Treatment Response for Each Bleeding Episode
Hide Description

Participants rated the treatment of each bleeding episode. If treatment occurred under direct supervision of treating physician, the physician rated the response.

Ratings based on a 4 point scale; EXCELLENT - full relief of pain and cessation of objective signs of bleeding (swelling, tenderness, decrease in range of motion [for muscle bleeds]) within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen.

GOOD - Substantial relief of pain and/or cessation of objective signs of bleeding within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen.

MODERATE - slight relief of pain and slight improvement of signs of bleeding within 9 hours of treatment initiation. Requires additional infusion beyond treatment regimen.

NONE - No improvement or condition worsens. SUCCESSFUL = EXCELLENT or GOOD.

Time Frame within 24 hours of infusion
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Dataset
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description:
Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions.
Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Overall Number of Participants Analyzed 18 20
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes
289 256
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent of bleeding episodes
Successful
87.89
(83.62 to 91.16)
79.30
(73.92 to 83.81)
Excellent
34.60
(29.35 to 40.26)
36.72
(31.05 to 42.78)
Good
53.29
(47.53 to 58.96)
42.58
(36.67 to 48.70)
Moderate
9.69
(6.79 to 13.65)
18.36
(14.10 to 23.56)
No Assessment Available
0
(0 to 0)
0.39
(0.07 to 2.18)
None
2.42
(1.18 to 4.91)
1.95
(0.84 to 4.49)
3.Secondary Outcome
Title Percentage of Clinical Responders (Sustained Bleeding Control) for All Acute Bleeding Episodes
Hide Description Clinical responders defined as sustained bleeding control, (no additional hemostatic medication including rFVIIa BI required between 12 and 24 hours after first infusion of the successfully treated bleeding episode).
Time Frame 24 hours post infusion
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Dataset
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description:
Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions.
Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Overall Number of Participants Analyzed 18 20
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes
289 256
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percent of bleeding episodes
93.43
(89.96 to 95.75)
76.17
(70.59 to 80.98)
4.Secondary Outcome
Title Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs)
Hide Description

Safety was determined by the number of AEs (both serious AEs [SAEs] and non-serious AEs [nsAE]).

Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judged the AE to be "possibly related" or "probably related" to rFVIIa BI.

The percentage of participants with AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related to rFVIIa BI).

Time Frame 6 months (throughout study period)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Dataset
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description:
Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions.
Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Overall Number of Participants Analyzed 18 20
Measure Type: Number
Unit of Measure: percent of participants with AEs
SAE-Moderate-Unrelated 5.6 5.0
SAE-Severe-Unrelated 11.1 0
SAE-Severe-Related 0 5
nsAE-Mild-Unrelated 22.2 30.0
nsAE-Moderate-Unrelated 0 15
5.Secondary Outcome
Title Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs)
Hide Description

Safety was determined by the number of AEs (both serious AEs [SAEs] and non-serious AEs [nsAE]).

Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judges the AE to be "possibly related" or "probably related" to rFVIIa BI.

The percentage of AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related [to rFVIIa BI]).

Time Frame 6 months (throughout study period)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Dataset
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description:
Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions.
Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Overall Number of Participants Analyzed 18 20
Overall Number of Units Analyzed
Type of Units Analyzed: Adverse events
15 16
Measure Type: Number
Unit of Measure: percent of AEs
SAE-Moderate-Unrelated 6.7 6.3
SAE-Severe-Unrelated 20.0 0
SAE-Severe-Related 0 12.5
nsAE-Mild-Unrelated 73.3 62.5
nsAE-Moderate-Unrelated 0 18.8
6.Secondary Outcome
Title Percentage of Participants With Inhibitor Development to FVII
Hide Description Development of rFVII inhibitors or FVIIa binding antibodies during the study.
Time Frame 6 months (throughout study period)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Dataset
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description:
Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions.
Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
Overall Number of Participants Analyzed 18 20
Measure Type: Number
Unit of Measure: percent of participants
0 0
Time Frame 6 months (throughout study period)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Hide Arm/Group Description Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) every 3 hours as on-demand intravenous bolus infusions. Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion.
All-Cause Mortality
Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/18 (11.11%)      2/20 (10.00%)    
General disorders     
Drug Ineffective * 1  0/18 (0.00%)  0 1/20 (5.00%)  1
Injury, poisoning and procedural complications     
Craniocerebral injury * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Joint injury * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Head Injury * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Limb Injury * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscle Haemorrhage * 1  0/18 (0.00%)  0 2/20 (10.00%)  2
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 17.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Arm 2: 1 x 270 Micrograms/kg rFVIIa BI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/18 (22.22%)      2/20 (10.00%)    
General disorders     
Pyrexia * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Immune system disorders     
Drug Hypersensitivity * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Infections and infestations     
Influenza * 1  0/18 (0.00%)  0 2/20 (10.00%)  2
Nasopharyngitis * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Tinea Versicolour * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Injury, poisoning and procedural complications     
Laceration * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Investigations     
Hepatic Enzyme Increased  1  1/18 (5.56%)  1 0/20 (0.00%)  0
Nervous system disorders     
Headache * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Sinus Headache * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Nasal Congestion * 1  1/18 (5.56%)  1 0/20 (0.00%)  0
Oropharyngeal Pain * 1  1/18 (5.56%)  2 0/20 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 17.1
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.
Baxalta's agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, results may not be published without prior written approval of Sponsor.
Results Point of Contact
Name/Title: Clinical Trial Registries and Results Disclosure
Organization: Baxalta US Inc.
Responsible Party: Shire ( Baxalta now part of Shire )
ClinicalTrials.gov Identifier: NCT01757405     History of Changes
Other Study ID Numbers: 021101
2011-006294-26 ( EudraCT Number )
First Submitted: December 21, 2012
First Posted: December 28, 2012
Results First Submitted: August 31, 2016
Results First Posted: October 25, 2016
Last Update Posted: October 23, 2017