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Phase III Study of Coagulation FVIIa (Recombinant) in Congenital Hemophilia A or B Patients With Inhibitors

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ClinicalTrials.gov Identifier: NCT02020369
Recruitment Status : Completed
First Posted : December 24, 2013
Results First Posted : June 14, 2017
Last Update Posted : June 14, 2017
Sponsor:
Collaborator:
Laboratoire français de Fractionnement et de Biotechnologies
Information provided by (Responsible Party):
rEVO Biologics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Hemophilia A With Inhibitors
Hemophilia B With Inhibitors
Intervention Biological: Coagulation Factor VIIa (Recombinant)
Enrollment 27
Recruitment Details  
Pre-assignment Details  
Arm/Group Title FVIIa: 225 µg/kg First, Then 75 µg/kg FVIIa: 75 µg/kg First, Then 225 µg/kg
Hide Arm/Group Description Coagulation Factor VIIa (Recombinant) : First Intervention (3 months), Second Intervention (3 months), repeat sequence for entirety of study. Coagulation Factor VIIa (Recombinant): Coagulation Factor VIIa (Recombinant) : First Intervention (3 months), Second Intervention (3 months), repeat sequence for entirety of study.
Period Title: Overall Study
Started 14 13
Completed 11 11
Not Completed 3 2
Arm/Group Title FVIIa 75 µg/kg First, Then 225 µg/kg FVIIa 225 µg/kg First, Then 75 µg/kg Total
Hide Arm/Group Description Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), continue cycle until end of study. Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), continue cycle until end of study. Total of all reporting groups
Overall Number of Baseline Participants 13 14 27
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants 14 participants 27 participants
<=18 years
2
  15.4%
3
  21.4%
5
  18.5%
Between 18 and 65 years
11
  84.6%
11
  78.6%
22
  81.5%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 13 participants 14 participants 27 participants
31.8  (12.10) 30.1  (12.98) 31.0  (12.35)
Sex/Gender, Customized  
Measure Type: Number
Unit of measure:  Participants
Male (n) Number Analyzed 13 participants 14 participants 27 participants
13 14 27
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants 14 participants 27 participants
Hispanic or Latino
1
   7.7%
0
   0.0%
1
   3.7%
Not Hispanic or Latino
12
  92.3%
14
 100.0%
26
  96.3%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants 14 participants 27 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   7.7%
0
   0.0%
1
   3.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
1
   7.1%
1
   3.7%
White
12
  92.3%
13
  92.9%
25
  92.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 13 participants 14 participants 27 participants
Russian Federation 2 3 5
United States 2 2 4
Ukraine 6 6 12
Poland 1 0 1
United Kingdom 0 1 1
Georgia 1 1 2
Bulgaria 1 1 2
1.Primary Outcome
Title Proportion of Successfully Treated Mild/Moderate Bleeding Episodes
Hide Description

For the primary efficacy endpoint, successful treatment of a bleeding episode was defined as a combination of the following:

  • “Good” or “Excellent” response noted by the patient
  • Study drug treatment: No further treatment with study drug beyond timepoint for this bleeding episode
  • No other hemostatic treatment needed for this bleeding episode
  • No administration of blood products that would indicate continuation of bleeding beyond timepoint
  • No increase of pain beyond timepoint that could not otherwise be explained
Time Frame 12 hours after first administration of study drug
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Population
Arm/Group Title FVIIa 75 µg/kg FVIIa 225µg/kg
Hide Arm/Group Description:
75 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
225 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
Overall Number of Participants Analyzed 25 25
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes (BEs)
252 213
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Proportion of Success of BEs
.849
(.740 to .957)
.932
(.881 to .983)
2.Secondary Outcome
Title Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported “Good” or “Excellent” Responses at 12 Hours
Hide Description

Based on Patient-Reported "Good" or "Excellent" responses as per the below descriptions:

Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug.

Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required.

Time Frame at 12 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Population
Arm/Group Title FVIIa: 75 µg/kg FVIIa: 225 µg/kg
Hide Arm/Group Description:
75 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
225 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
Overall Number of Participants Analyzed 25 25
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes (BEs)
252 213
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Pt-reported proportion success of BEs
0.857
(0.750 to 0.964)
0.937
(0.888 to 0.986)
3.Secondary Outcome
Title Time to Assessment of a “Good” or “Excellent” Response of Mild/Moderate Bleeding Episodes by the Patient
Hide Description

Categories of Response to Treatment are Described as Follows:

None: No noticeable effect of the treatment on the bleed or worsening of patient’s condition. Continuation of treatment with the study drug was needed.

Moderate: Some effect of the treatment on the bleed was noticed, e.g., pain decreased or bleeding signs improved, but bleed continued and required continued treatment with the study drug. Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug.

Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required.

Time Frame Within 24 hours of Bleeding Episode
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Population with non-missing measurements
Arm/Group Title FVIIa: 75 µg/kg FVIIa: 225 µg/kg
Hide Arm/Group Description:
75 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
225 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
Overall Number of Participants Analyzed 25 25
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes with event
240 208
Median (95% Confidence Interval)
Unit of Measure: Hours
5.98
(5.95 to 6.00)
3.00 [1] 
(NA to NA)
[1]
The confidence interval (CI) for the median time is a pointwise CI. The median was 3 hours and approximately 30% of bleeding episodes had good/excellent response exactly at 3 hours which made the confidence limits non-calculable.
4.Secondary Outcome
Title Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode
Hide Description [Not Specified]
Time Frame Within 24 hours of Bleeding Episode
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Population with non-missing measurements
Arm/Group Title Factor VIIa: 75 µg/kg FVIIa: 225 µg/kg
Hide Arm/Group Description:
75 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
225 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
Overall Number of Participants Analyzed 25 25
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding episodes
252 211
Mean (Standard Deviation)
Unit of Measure: Number of Administrations of Study Drug
2.5  (1.75) 1.4  (0.96)
5.Secondary Outcome
Title Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode
Hide Description [Not Specified]
Time Frame Through study completion
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Population with non-missing measurements
Arm/Group Title FVIIa: 75 µg/kg FVIIa: 225 µg/kg
Hide Arm/Group Description:
75 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
225 µg/kg Treatment Regimen at Time of Mild/Moderate Bleeding Episode
Overall Number of Participants Analyzed 25 25
Overall Number of Units Analyzed
Type of Units Analyzed: Bleeding Episodes
251 211
Mean (Standard Deviation)
Unit of Measure: µg/kg per bleeding episode
187.868  (131.7982) 252.963  (78.9732)
Time Frame Adverse event data was collected 2 years, 3 months, 2 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Coagulation Factor VIIa (Recombinant): 75 µg/kg Coagulation Factor VIIa (Recombinant): 225 µg/kg
Hide Arm/Group Description

Coagulation Factor VIIa (Recombinant): 75 µg/kg for 3 months

Coagulation Factor VIIa (Recombinant): A cross over design to assess the efficacy of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX

Coagulation Factor VIIa (Recombinant) : 225 µg/kg for 3 months

Coagulation Factor VIIa (Recombinant): A cross over design to assess the efficacy of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX

All-Cause Mortality
Coagulation Factor VIIa (Recombinant): 75 µg/kg Coagulation Factor VIIa (Recombinant): 225 µg/kg
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Coagulation Factor VIIa (Recombinant): 75 µg/kg Coagulation Factor VIIa (Recombinant): 225 µg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/25 (4.00%)      0/25 (0.00%)    
Infections and infestations     
acute tonsillitis  1  1/25 (4.00%)  1 0/25 (0.00%)  0
Nervous system disorders     
subarachnoid hemorrhage  1  1/25 (4.00%)  1 0/25 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Coagulation Factor VIIa (Recombinant): 75 µg/kg Coagulation Factor VIIa (Recombinant): 225 µg/kg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/25 (12.00%)      3/25 (12.00%)    
Infections and infestations     
Nasopharyngitis  1  1/25 (4.00%)  1 2/25 (8.00%)  2
Nervous system disorders     
Headache  1  2/25 (8.00%)  3 1/25 (4.00%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
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.
Results Point of Contact
Name/Title: Jeffry Lawrence, MD, Vice President, Clinical Development
Organization: LFB USA Inc.
Phone: +1.508.370.5113
Responsible Party: rEVO Biologics
ClinicalTrials.gov Identifier: NCT02020369     History of Changes
Other Study ID Numbers: RB-FVIIa-006-13
First Submitted: December 18, 2013
First Posted: December 24, 2013
Results First Submitted: July 12, 2016
Results First Posted: June 14, 2017
Last Update Posted: June 14, 2017