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A Safety, Tolerability, and Pharmacokinetics Study of a Single Intravenous Injection of Recombinant Coagulation Factor VIII Fc - Von Willebrand Factor - XTEN Fusion Protein (rFVIIIFc-VWF-XTEN) (BIVV001) in Previously Treated Adults With Severe Hemophilia A (EXTEN-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: NCT03205163
Recruitment Status : Completed
First Posted : July 2, 2017
Results First Posted : December 2, 2019
Last Update Posted : April 19, 2022
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Bioverativ, a Sanofi company )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Other
Condition Hemophilia A
Interventions Biological: Advate (Low Dose)
Biological: Advate (High Dose)
Biological: BIVV001 (Low Dose)
Biological: BIVV001 (High Dose)
Enrollment 16
Recruitment Details The study was conducted in Japan and United States between 28 August 2017 to 12 November 2018.
Pre-assignment Details A total of 16 participants were enrolled, 7 participants to low dose cohort (LDC) and 9 to high dose cohort (HDC).
Arm/Group Title Low Dose Cohort (LDC): Advate 25 IU/kg Then BIVV001 25 IU/kg High Dose Cohort (HDC): Advate 65 IU/kg Then BIVV001 65 IU/kg
Hide Arm/Group Description Participants received a single intravenous (IV) dose of Advate 25 International Units per kilogram (IU/kg) on Day 1 of Advate treatment period (ATP) (3 days) followed by a single IV dose of BIVV001 25 IU/kg in BIVV001 treatment period (BTP) (28 days). ATP consisted of a washout of at least 72 hours which was started from the time of Advate dosing. Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days) followed by a single IV dose of BIVV001 65 IU/kg in BTP (28 days). ATP consisted of a washout of at least 96 hours which was started from the time of Advate dosing.
Period Title: ATP (LDC: 3 Days; HDC: 4 Days)
Started 7 9
Safety Population 7 9
Completed 6 9
Not Completed 1 0
Reason Not Completed
Sponsor Decision             1             0
Period Title: BTP (LDC: 28 Days; HDC: 28 Days)
Started 6 9
Safety Population 6 9
Completed 6 9
Not Completed 0 0
Arm/Group Title LDC: Advate 25 IU/kg Then BIVV001 25 IU/kg HDC: Advate 65 IU/kg Then BIVV001 65 IU/kg Total
Hide Arm/Group Description Participants received a single IV dose of Advate 25 IU/kg on Day 1 of ATP (3 days) followed by a single IV dose of BIVV001 25 IU/kg in BTP (28 days). ATP consisted of a washout of at least 72 hours which was started from the time of Advate dosing. Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days) followed by a single IV dose of BIVV001 65 IU/kg in BTP (28 days). ATP consisted of a washout of at least 96 hours which was started from the time of Advate dosing. Total of all reporting groups
Overall Number of Baseline Participants 7 9 16
Hide Baseline Analysis Population Description
Baseline population included all enrolled participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 9 participants 16 participants
33.0  (13.81) 44.0  (11.65) 39.2  (13.43)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 9 participants 16 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
7
 100.0%
9
 100.0%
16
 100.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 9 participants 16 participants
American Indian or Alaska Native
0
   0.0%
1
  11.1%
1
   6.3%
Asian
1
  14.3%
1
  11.1%
2
  12.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
6
  85.7%
7
  77.8%
13
  81.3%
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%
1.Primary Outcome
Title Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period
Hide Description AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the single dose of Advate but before the single dose of BIVV001. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
Time Frame Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety analysis set which included all participants who received at least 1 dose of Advate.
Arm/Group Title Advate 25 IU/kg Advate 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 of ATP (3 days).
Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days).
Overall Number of Participants Analyzed 7 9
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE
2
  28.6%
1
  11.1%
TESAE
1
  14.3%
0
   0.0%
2.Primary Outcome
Title Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period
Hide Description AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the study treatment (BIVV001) and within 28 days after BIVV001 administration. SAE was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
Time Frame Up to 28 days after BIVV001 administration
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety analysis set which included all participants who received at least 1 dose of BIVV001.
Arm/Group Title BIVV001 25 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 6 9
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE
3
  50.0%
6
  66.7%
TESAE
1
  16.7%
0
   0.0%
3.Primary Outcome
Title Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period
Hide Description Number of Participants with Clinically Significant Abnormalities in Laboratory tests (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
Time Frame Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety analysis set.
Arm/Group Title Advate 25 IU/kg Advate 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 of ATP (3 days).
Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days).
Overall Number of Participants Analyzed 7 9
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
4.Primary Outcome
Title Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period
Hide Description Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
Time Frame Up to 28 days after BIVV001 administration
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety analysis set.
Arm/Group Title BIVV001 25 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 6 9
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
5.Primary Outcome
Title Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay
Hide Description Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample, collected within 2 to 4 weeks of the first positive sample, with both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.
Time Frame Up to 28 days after BIVV001 administration
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety analysis set.
Arm/Group Title Low Dose Cohort (LDC): Advate 25 IU/kg Then BIVV001 25 IU/kg High Dose Cohort (HDC): Advate 65 IU/kg Then BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 of ATP (3 days) followed by a single IV dose of BIVV001 25 IU/kg in BTP (28 days). ATP consisted of a washout of at least 72 hours which was started from the time of Advate dosing.
Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days) followed by a single IV dose of BIVV001 65 IU/kg in BTP (28 days). Advate treatment period consisted of a washout of at least 96 hours which was started from the time of Advate dosing.
Overall Number of Participants Analyzed 7 9
Measure Type: Number
Unit of Measure: percentage of participants
0 0
6.Secondary Outcome
Title Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison)
Hide Description Cmax of Advate and BIVV001 at low dose was assessed and compared based on One-stage activated partial thromboplastin time (aPTT)-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on pharmacokinetic analysis set (PKAS) which included participants who had adequate blood sample collections (following Advate or BIVV001 administration), to assess key PK parameters, as determined by the PK scientist.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: International unit/deciliter (IU/dL)
51.8
(43.3 to 61.9)
70.1
(49.7 to 98.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an analysis of variance (ANOVA) model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and geometric mean ratio (GMR) were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.032
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 1.35
Confidence Interval (2-Sided) 95%
1.04 to 1.77
Estimation Comments [Not Specified]
7.Secondary Outcome
Title PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison)
Hide Description Cmax of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/dL
138
(117 to 162)
161
(142 to 183)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 1.17
Confidence Interval (2-Sided) 95%
1.09 to 1.25
Estimation Comments [Not Specified]
8.Secondary Outcome
Title PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison)
Hide Description Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
9.12
(6.24 to 13.33)
37.61
(33.28 to 42.50)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 4.13
Confidence Interval (2-Sided) 95%
2.94 to 5.79
Estimation Comments [Not Specified]
9.Secondary Outcome
Title PK: Half-Life for Advate and BIVV001 (High Dose Comparison)
Hide Description Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
13.15
(10.89 to 15.87)
42.54
(39.72 to 45.56)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 3.24
Confidence Interval (2-Sided) 95%
2.76 to 3.79
Estimation Comments [Not Specified]
10.Secondary Outcome
Title PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison)
Hide Description Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: milliliter/hour/kilogram (mL/hr/kg)
3.91
(3.05 to 5.02)
0.558
(0.411 to 0.757)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 0.143
Confidence Interval (2-Sided) 95%
0.118 to 0.172
Estimation Comments [Not Specified]
11.Secondary Outcome
Title PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison)
Hide Description Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: mL/hr/kg
3.31
(2.81 to 3.88)
0.505
(0.436 to 0.586)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 0.153
Confidence Interval (2-Sided) 95%
0.138 to 0.170
Estimation Comments [Not Specified]
12.Secondary Outcome
Title PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison)
Hide Description Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: milliliter/kilogram (mL/kg)
55.9
(51.2 to 61.0)
34.8
(27.3 to 44.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 0.622
Confidence Interval (2-Sided) 95%
0.492 to 0.786
Estimation Comments [Not Specified]
13.Secondary Outcome
Title PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison)
Hide Description Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: mL/kg
58.3
(49.8 to 68.2)
35.0
(29.7 to 41.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 0.599
Confidence Interval (2-Sided) 95%
0.525 to 0.684
Estimation Comments [Not Specified]
14.Secondary Outcome
Title PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison)
Hide Description AUCinfinity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: hour*international unit/deciliter
638
(495 to 822)
4470
(3280 to 6080)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 7.00
Confidence Interval (2-Sided) 95%
5.78 to 8.48
Estimation Comments [Not Specified]
15.Secondary Outcome
Title PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison)
Hide Description AUCinfinity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: hour*international unit/deciliter
1960
(1670 to 2310)
12800
(11100 to 14900)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 6.54
Confidence Interval (2-Sided) 95%
5.89 to 7.27
Estimation Comments [Not Specified]
16.Secondary Outcome
Title PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison)
Hide Description The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
12.54
(9.82 to 16.01)
56.93
(49.19 to 65.89)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 4.54
Confidence Interval (2-Sided) 95%
3.64 to 5.66
Estimation Comments [Not Specified]
17.Secondary Outcome
Title PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison)
Hide Description The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
15.66
(14.06 to 17.45)
67.66
(62.59 to 73.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 4.32
Confidence Interval (2-Sided) 95%
3.96 to 4.72
Estimation Comments [Not Specified]
18.Secondary Outcome
Title PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison)
Hide Description Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/dL per IU/kg
2.0
(1.60 to 2.50)
2.72
(1.95 to 3.80)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.063
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 1.36
Confidence Interval (2-Sided) 95%
0.978 to 1.89
Estimation Comments [Not Specified]
19.Secondary Outcome
Title PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison)
Hide Description Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/dL per IU/kg
2.11
(1.79 to 2.49)
2.48
(2.18 to 2.82)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 1.18
Confidence Interval (2-Sided) 95%
1.10 to 1.26
Estimation Comments [Not Specified]
20.Secondary Outcome
Title PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison)
Hide Description Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 25 IU/kg BIVV001 25 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 25 IU/kg on Day 1 in ATP (3 days).
Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 7 6
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
56.97
(49.25 to 65.89)
260.53
(222.34 to 305.30)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 25 IU/kg, BIVV001 25 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 4.57
Confidence Interval (2-Sided) 95%
4.00 to 5.23
Estimation Comments [Not Specified]
21.Secondary Outcome
Title PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison)
Hide Description Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
Time Frame For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on PKAS.
Arm/Group Title Advate 65 IU/kg BIVV001 65 IU/kg
Hide Arm/Group Description:
Participants received a single IV dose of Advate 65 IU/kg on Day 1 in ATP (4 days).
Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
Overall Number of Participants Analyzed 9 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: hours
78.48
(70.88 to 86.89)
350.34
(326.61 to 375.81)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Advate 65 IU/kg, BIVV001 65 IU/kg
Comments Comparison of Advate and BIVV001 was obtained through analyzing log transformed PK parameters using an ANOVA model containing participant and treatment as factors. Geometric mean, 95% confidence interval of geometric mean, and GMR were the exponentiated mean, 95% confidence interval, and difference of means, respectively.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter GMR
Estimated Value 4.46
Confidence Interval (2-Sided) 95%
4.16 to 4.79
Estimation Comments [Not Specified]
Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (28 days after BIVV001 administration) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description Analysis was performed on safety analysis set.
 
Arm/Group Title Advate Dose Level: 25 IU/kg Advate Dose Level: 65 IU/kg BIVV001 Dose Level: 25 IU/kg BIVV001 Dose Level: 65 IU/kg
Hide Arm/Group Description Participants received a single IV dose of Advate 25 IU/kg on Day 1 of ATP (3 days). Participants received a single IV dose of Advate 65 IU/kg on Day 1 of ATP (4 days). Participants received a single IV dose of BIVV001 25 IU/kg on Day 1 in BTP (28 days). Participants received a single IV dose of BIVV001 65 IU/kg on Day 1 in BTP (28 days).
All-Cause Mortality
Advate Dose Level: 25 IU/kg Advate Dose Level: 65 IU/kg BIVV001 Dose Level: 25 IU/kg BIVV001 Dose Level: 65 IU/kg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/7 (0.00%)   0/9 (0.00%)   0/6 (0.00%)   0/9 (0.00%) 
Hide Serious Adverse Events
Advate Dose Level: 25 IU/kg Advate Dose Level: 65 IU/kg BIVV001 Dose Level: 25 IU/kg BIVV001 Dose Level: 65 IU/kg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/7 (14.29%)   0/9 (0.00%)   1/6 (16.67%)   0/9 (0.00%) 
Gastrointestinal disorders         
Small intestinal obstruction  1  0/7 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/9 (0.00%) 
Injury, poisoning and procedural complications         
Contusion  1  1/7 (14.29%)  0/9 (0.00%)  0/6 (0.00%)  0/9 (0.00%) 
Road traffic accident  1  1/7 (14.29%)  0/9 (0.00%)  0/6 (0.00%)  0/9 (0.00%) 
Musculoskeletal and connective tissue disorders         
Haemarthrosis  1  1/7 (14.29%)  0/9 (0.00%)  0/6 (0.00%)  0/9 (0.00%) 
Tendonitis  1  1/7 (14.29%)  0/9 (0.00%)  0/6 (0.00%)  0/9 (0.00%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Advate Dose Level: 25 IU/kg Advate Dose Level: 65 IU/kg BIVV001 Dose Level: 25 IU/kg BIVV001 Dose Level: 65 IU/kg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/7 (14.29%)   1/9 (11.11%)   3/6 (50.00%)   6/9 (66.67%) 
Cardiac disorders         
Palpitations  1  0/7 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/9 (11.11%) 
Gastrointestinal disorders         
Diarrhoea  1  0/7 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/9 (0.00%) 
Gingival pain  1  0/7 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/9 (0.00%) 
Infections and infestations         
Nasopharyngitis  1  0/7 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/9 (11.11%) 
Viral upper respiratory tract infection  1  0/7 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/9 (11.11%) 
Injury, poisoning and procedural complications         
Joint injury  1  0/7 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/9 (11.11%) 
Limb injury  1  0/7 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/9 (11.11%) 
Investigations         
Coagulation test abnormal  1  1/7 (14.29%)  0/9 (0.00%)  0/6 (0.00%)  0/9 (0.00%) 
Fibrin d dimer increased  1  0/7 (0.00%)  1/9 (11.11%)  0/6 (0.00%)  1/9 (11.11%) 
Thrombin-antithrombin iii complex increased  1  1/7 (14.29%)  1/9 (11.11%)  1/6 (16.67%)  1/9 (11.11%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  0/7 (0.00%)  0/9 (0.00%)  0/6 (0.00%)  1/9 (11.11%) 
Pain in jaw  1  0/7 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  0/9 (0.00%) 
Nervous system disorders         
Headache  1  0/7 (0.00%)  0/9 (0.00%)  1/6 (16.67%)  1/9 (11.11%) 
1
Term from vocabulary, MedDRA 21.0
Indicates events were collected by systematic assessment
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.
The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Trial Transparency Team
Organization: Bioverativ, a Sanofi company
Phone: 800-633-1610 ext 6
EMail: Contact-US@sanofi.com
Layout table for additonal information
Responsible Party: Sanofi ( Bioverativ, a Sanofi company )
ClinicalTrials.gov Identifier: NCT03205163    
Other Study ID Numbers: TDU16220
242HA101 ( Other Identifier: Bioverativ, a Sanofi company )
First Submitted: June 29, 2017
First Posted: July 2, 2017
Results First Submitted: November 11, 2019
Results First Posted: December 2, 2019
Last Update Posted: April 19, 2022