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)
Sponsor
Bioverativ, a Sanofi company (Industry)
Overall Status
Completed
CT.gov ID
NCT03205163
Collaborator
(none)
16
10
2
14.5
1.6
0.1
Study Details
Study Description
Brief Summary
The primary purpose was to assess the safety and tolerability of a single intravenous (IV) administration of BIVV001 in adult previously treated patients (PTPs) with severe hemophilia A.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
16 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Phase 1/2a, Open-Label, Dose-Escalation Study to Determine the Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Injection of rFVIIIFc-VWF-XTEN (BIVV001) in Previously Treated Adults With Severe Hemophilia A
Actual Study Start Date
:
Aug 28, 2017
Actual Primary Completion Date
:
Nov 12, 2018
Actual Study Completion Date
:
Nov 12, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Low Dose Cohort: Advate 25 IU/kg Then BIVV001 25 IU/kg Participants received a single intravenous (IV) dose of Advate 25 international units per kilogram (IU/kg) on Day 1 of Advate treatment period (3 days) followed by a single IV dose of BIVV001 25 IU/kg in BIVV001 treatment period (BTP) (28 days). Advate treatment period (ATP) consisted of a washout of at least 72 hours which was started from the time of Advate dosing. |
Biological: Advate (Low Dose)
Participants received a single IV low dose of Advate 25 IU/kg.
Biological: BIVV001 (Low Dose)
Participants received single IV low dose of BIVV001 25 IU/kg.
|
| Experimental: High Dose Cohort: Advate 65 IU/kg Then BIVV001 65 IU/kg 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. |
Biological: Advate (High Dose)
Participants received a single IV high dose of Advate 65 IU/kg.
Biological: BIVV001 (High Dose)
Participants received single IV high dose of BIVV001 65 IU/kg.
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period [Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg]
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.
- Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period [Up to 28 days after BIVV001 administration]
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.
- Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period [Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg]
Number of Participants with Clinically Significant Abnormalities in Laboratory tests (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
- Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period [Up to 28 days after BIVV001 administration]
Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
- Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay [Up to 28 days after BIVV001 administration]
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.
Secondary Outcome Measures
- Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) [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]
Cmax of Advate and BIVV001 at low dose was assessed and compared based on One-stage activated partial thromboplastin time (aPTT)-based clotting assay.
- PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) [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]
Cmax of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
- PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) [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]
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.
- PK: Half-Life for Advate and BIVV001 (High Dose Comparison) [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]
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.
- PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) [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]
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.
- PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) [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]
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.
- PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) [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]
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.
- PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) [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]
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.
- PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) [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]
AUCinfinity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
- PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) [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]
AUCinfinity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
- PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) [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]
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.
- PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) [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]
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.
- PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) [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]
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.
- PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) [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]
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.
- PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) [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]
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.
- PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) [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]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 65 Years
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Ability of the participant, or his legally authorized representative (e.g., parent or legal guardian) if applicable in accordance with local regulations, to understand the purpose and risks of the study and provide signed and dated informed consent/assent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
-
Severe hemophilia A, defined as less than (<) 1 international units per deciliter (IU/dL) (<1 percent [%]) endogenous FVIII at screening as determined by the one-stage clotting assay from the central laboratory. If the initial screening result was greater than or equal to (>=) 1%, then a repeat endogenous FVIII activity level was performed using the one stage clotting assay from the central laboratory. If the repeated result was < 1 IU/dL (<1%), then the participant met this inclusion requirement.
-
Previous treatment for hemophilia A, defined as at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days.
-
Platelet count >=100,000 cells/ microliter (mcL) at screening (test performed by the central laboratory and reviewed prior to the Day 1 Advate dose).
-
A participant known to be human immunodeficiency virus (HIV) antibody positive, either previously documented or identified from screening assessments, must have the following results prior to Day 1 Advate dose: cluster of differentiation 4 (CD4) lymphocyte count greater than (>) 200 cells/millimeter (mm)^3; viral load of <400 copies/mL.
Exclusion Criteria:
Medical History:
-
Any concurrent clinically significant major disease that, in the opinion of the Investigator, made the participant unsuitable for enrollment.
-
Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present within 30 days of screening.
-
Other known coagulation disorder(s) in addition to hemophilia A.
-
History of hypersensitivity or anaphylaxis associated with any FVIII product.
-
Known or suspected allergy to mice, hamsters, or any ingredient in Advate.
-
History of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors not excluded the participant.
Medications and Procedures:
- Current enrollment or participation within 30 days prior to screening in any other investigational study.
Other:
-
Inability to comply with study requirements as assessed by the Investigator.
-
Other unspecified reasons that, in the opinion of the Investigator or Sponsor, made the participant unsuitable for enrollment.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California Los Angeles Medical Center | Los Angeles | California | United States | 90007 |
| 2 | Indiana Hemophilia and Thrombosis Center | Indianapolis | Indiana | United States | 46260 |
| 3 | University of Iowa Hospitals & Clinics | Iowa City | Iowa | United States | 52242 |
| 4 | Michigan State University | East Lansing | Michigan | United States | 48823 |
| 5 | Mississippi Center for Advanced Medicine | Madison | Mississippi | United States | 39110 |
| 6 | Hemophilia Center of Western PA | Pittsburgh | Pennsylvania | United States | 15213 |
| 7 | University of Washington | Seattle | Washington | United States | 98104 |
| 8 | Nara Medical University Hospital | Kashihara-Shi | Nara-Ken | Japan | 634-8521 |
| 9 | Tokyo Medical University Hospital | Shinjuku-Ku | Tokyo-To | Japan | 160-0023 |
| 10 | Ogikubo Hospital | Tokyo | Tokyo-To | Japan | 167-8515 |
Sponsors and Collaborators
- Bioverativ, a Sanofi company
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Bioverativ, a Sanofi company
ClinicalTrials.gov Identifier:
NCT03205163
Other Study ID Numbers:
- TDU16220
- 242HA101
First Posted:
Jul 2, 2017
Last Update Posted:
Apr 19, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted in Japan and United States between 28 August 2017 to 12 November 2018. |
|---|---|
| Pre-assignment Detail | 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 |
|---|---|---|
| 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 |
| Period Title: ATP (LDC: 3 Days; HDC: 4 Days) | ||
| STARTED | 6 | 9 |
| Safety Population | 6 | 9 |
| COMPLETED | 6 | 9 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | LDC: Advate 25 IU/kg Then BIVV001 25 IU/kg | HDC: Advate 65 IU/kg Then BIVV001 65 IU/kg | Total |
|---|---|---|---|
| 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 Participants | 7 | 9 | 16 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
33.0
(13.81)
|
44.0
(11.65)
|
39.2
(13.43)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
0
0%
|
0
0%
|
| Male |
7
100%
|
9
100%
|
16
100%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
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%
|
| Black or African American |
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%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
| Title | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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). |
| Measure Participants | 7 | 9 |
| TEAE |
2
28.6%
|
1
11.1%
|
| TESAE |
1
14.3%
|
0
0%
|
| Title | Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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). |
| Measure Participants | 6 | 9 |
| TEAE |
3
42.9%
|
6
66.7%
|
| TESAE |
1
14.3%
|
0
0%
|
| Title | Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety analysis set. |
| Arm/Group Title | Advate 25 IU/kg | Advate 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 9 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
| Title | Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety analysis set. |
| Arm/Group Title | BIVV001 25 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 6 | 9 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
| Title | Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 7 | 9 |
| Number [percentage of participants] |
0
0%
|
0
0%
|
| Title | Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [International unit/deciliter (IU/dL)] |
51.8
|
70.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 65 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 | ||
| Statistical Test of Hypothesis | p-Value | 0.032 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 1.35 | |
| Confidence Interval |
(2-Sided) 95% 1.04 to 1.77 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [IU/dL] |
138
|
161
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 1.17 | |
| Confidence Interval |
(2-Sided) 95% 1.09 to 1.25 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [hours] |
9.12
|
37.61
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 4.13 | |
| Confidence Interval |
(2-Sided) 95% 2.94 to 5.79 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Half-Life for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [hours] |
13.15
|
42.54
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 3.24 | |
| Confidence Interval |
(2-Sided) 95% 2.76 to 3.79 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [milliliter/hour/kilogram (mL/hr/kg)] |
3.91
|
0.558
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 0.143 | |
| Confidence Interval |
(2-Sided) 95% 0.118 to 0.172 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [mL/hr/kg] |
3.31
|
0.505
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 0.153 | |
| Confidence Interval |
(2-Sided) 95% 0.138 to 0.170 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [milliliter/kilogram (mL/kg)] |
55.9
|
34.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | 0.003 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 0.622 | |
| Confidence Interval |
(2-Sided) 95% 0.492 to 0.786 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [mL/kg] |
58.3
|
35.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 0.599 | |
| Confidence Interval |
(2-Sided) 95% 0.525 to 0.684 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [hour*international unit/deciliter] |
638
|
4470
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 7.00 | |
| Confidence Interval |
(2-Sided) 95% 5.78 to 8.48 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [hour*international unit/deciliter] |
1960
|
12800
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 6.54 | |
| Confidence Interval |
(2-Sided) 95% 5.89 to 7.27 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [hours] |
12.54
|
56.93
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 4.54 | |
| Confidence Interval |
(2-Sided) 95% 3.64 to 5.66 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [hours] |
15.66
|
67.66
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 4.32 | |
| Confidence Interval |
(2-Sided) 95% 3.96 to 4.72 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [IU/dL per IU/kg] |
2.0
|
2.72
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | 0.063 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 1.36 | |
| Confidence Interval |
(2-Sided) 95% 0.978 to 1.89 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [IU/dL per IU/kg] |
2.11
|
2.48
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 1.18 | |
| Confidence Interval |
(2-Sided) 95% 1.10 to 1.26 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 25 IU/kg | BIVV001 25 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 7 | 6 |
| Geometric Mean (95% Confidence Interval) [hours] |
56.97
|
260.53
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 4.57 | |
| Confidence Interval |
(2-Sided) 95% 4.00 to 5.23 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PKAS. |
| Arm/Group Title | Advate 65 IU/kg | BIVV001 65 IU/kg |
|---|---|---|
| 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). |
| Measure Participants | 9 | 8 |
| Geometric Mean (95% Confidence Interval) [hours] |
78.48
|
350.34
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Advate 25 IU/kg, Advate 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 | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | ||
| Method | ANOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | GMR |
| Estimated Value | 4.46 | |
| Confidence Interval |
(2-Sided) 95% 4.16 to 4.79 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| 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 | ||||
| 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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | ||||
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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/7 (14.3%) | 0/9 (0%) | 1/6 (16.7%) | 0/9 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Small intestinal obstruction | 0/7 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/9 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Contusion | 1/7 (14.3%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | ||||
| Road traffic accident | 1/7 (14.3%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Haemarthrosis | 1/7 (14.3%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | ||||
| Tendonitis | 1/7 (14.3%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | ||||
Other (Not Including 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 (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/7 (14.3%) | 1/9 (11.1%) | 3/6 (50%) | 6/9 (66.7%) | ||||
| Cardiac disorders | ||||||||
| Palpitations | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Gastrointestinal disorders | ||||||||
| Diarrhoea | 0/7 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/9 (0%) | ||||
| Gingival pain | 0/7 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/9 (0%) | ||||
| Infections and infestations | ||||||||
| Nasopharyngitis | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Viral upper respiratory tract infection | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Joint injury | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Limb injury | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Investigations | ||||||||
| Coagulation test abnormal | 1/7 (14.3%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | ||||
| Fibrin d dimer increased | 0/7 (0%) | 1/9 (11.1%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Thrombin-antithrombin iii complex increased | 1/7 (14.3%) | 1/9 (11.1%) | 1/6 (16.7%) | 1/9 (11.1%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 0/7 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||
| Pain in jaw | 0/7 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/9 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 0/7 (0%) | 0/9 (0%) | 1/6 (16.7%) | 1/9 (11.1%) | ||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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
| Name/Title | Trial Transparency Team |
|---|---|
| Organization | Bioverativ, a Sanofi company |
| Phone | 800-633-1610 ext 6 |
| Contact-US@sanofi.com |
Responsible Party:
Bioverativ, a Sanofi company
ClinicalTrials.gov Identifier:
NCT03205163
Other Study ID Numbers:
- TDU16220
- 242HA101
First Posted:
Jul 2, 2017
Last Update Posted:
Apr 19, 2022
Last Verified:
Mar 1, 2022