BAX 826 Dose-Escalation Safety Study
Sponsor
Baxalta now part of Shire (Industry)
Overall Status
Completed
CT.gov ID
NCT02716194
Collaborator
(none)
40
28
3
10.5
1.4
0.1
Study Details
Study Description
Brief Summary
-
To assess tolerability and safety of BAX 826 after a single infusion in previously treated patients (PTPs) with severe hemophilia A
-
To determine the pharmacokinetic (PK) parameters of BAX 826 compared to ADVATE
-
To evaluate immunogenicity of polysialic acid linked to Factor VIII (FVIII)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
40 participants
Allocation:
Non-Randomized
Intervention Model:
Crossover Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1, Prospective, Open Label, Two Period, Fixed Sequence, Dose-Escalation Study of the PK and Safety of BAX 826 (PSA-rFVIII) in Previously Treated Patients With Severe (FVIII <1%) Hemophilia A
Actual Study Start Date
:
Mar 3, 2016
Actual Primary Completion Date
:
Jan 17, 2017
Actual Study Completion Date
:
Jan 17, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1 - Low dose The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. |
Biological: BAX 826
Other Names:
Biological: Octocog alfa
Other Names:
|
| Experimental: Cohort 2 - Medium dose The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. |
Biological: BAX 826
Other Names:
Biological: Octocog alfa
Other Names:
|
| Experimental: Cohort 3 - High dose The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. |
Biological: BAX 826
Other Names:
Biological: Octocog alfa
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 [Up to 6 weeks ± 4 days post infusion with BAX826.]
Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826.
- Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) [Screening (Day -30 to -2); Advate Administration (Study Day 1) pre & postdose, and Day 4; Advate washout 96 hours to 4 weeks; BAX826 Administration Day 1 pre & postdose, Post BAX826 Day 4, 8, 14, and 23; and study termination visit, week 6 ± 4 days]
Clinically significant results after treatment with investigational product that constitute an AE are counted. Vital signs include body temperature, respiratory rate, pulse rate, and blood pressure. Clinical laboratory results include: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (i.e. basophils, eosinophils, lymphocytes, monocytes and neutrophils), international normalized ratio (INR), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count. Clinical Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, glucose. Lipid panel: cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides
- Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) [Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days]
Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay.
- Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) [Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days]
Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM
- Immunogenicity: Binding Antibodies to Factor VIII (FVIII) [Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days]
Binding antibodies to FVIII IgG and IgM
- Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies [Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days]
Binding antibodies to PSA (IgG and IgM)
- Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies [Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days]
Binding antibodies to CHO
- Immunogenicity: Human Anti-murine Antibodies (HAMA) [Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days]
Binding antibodies HAMA (IgG)
Secondary Outcome Measures
- Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Area under the FVIII activity-time curve from zero extrapolated to infinity, calculated by linear-up/log-down trapezoidal method and extrapolated to infinity, calculated as AUC last + C last / lambda z, where Clast is the estimated concentration at the last quantifiable time point
- Pharmacokinetics: Terminal Half-life (t1/2) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Terminal elimination phase half-life, calculated by (ln2)/lambda z, where lambda z is the terminal rate constant, determined by linear regression of the terminal points of the log-linear FVIII activity-time curve.
- Pharmacokinetics: Mean Residence Time (MRT) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion
- Pharmacokinetics: Total Body Clearance (CL) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞
- Pharmacokinetics: Incremental Recovery (IR) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg)
- Pharmacokinetics: Volume of Distribution at Steady State (Vss) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Volume of distribution at steady state is calculated by MRT*CL MRT=Mean residence time CL=Clearance rate
- Pharmacokinetics: Maximum Plasma Concentration (Cmax) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Maximum observed FVIII activity, obtained directly from FVIII activity versus time data
- Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Time of maximum FVIII activity is obtained directly from FVIII activity versus time data
- Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method.
- Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
AUC from time zero to exactly 72 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 72 hours is missing, the activity at 72 hours will be interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z).
- Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.]
AUC from time zero to exactly 168 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 168 hours is missing, the activity at 168 hours was interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). This parameter will be calculated for BAX 826 only.
- Comparison of Key Pharmacokinetic Parameters by Cohort [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.]
The key pharmacokinetic parameters (Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from 0 to 72 hours (AUC0-72h), Maximum plasma concentration (Cmax), Terminal half-life (t1/2), Mean residence time (MRT) and Total body clearance (CL)) for ADVATE and BAX 826 have been compared.
- Summary of Assessment of Dose Proportionality for BAX 826 [Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.]
Dose Proportionality for BAX 826 was calculated for the parameters Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from time 0 to the last quantifiable time point (AUC0-last) and Maximum plasma concentration (Cmax).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 65 Years
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Previously treated male participants aged 18 to 65 years (inclusive) at the time of screening
-
Diagnosis of severe hemophilia A (Factor VIII level <1%)
-
Previously treated with FVIII concentrates for ≥150 documented Exposure Days (EDs)
-
Karnofsky performance score of ≥60
-
Human immunodeficiency virus negative (HIV-); or HIV+ with stable disease
-
Hepatitis C virus negative (HCV-); or HCV+ with chronic stable hepatitis as assessed by the investigator
-
Able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an ethics committee (EC)
-
Have provided written authorization for use and disclosure of protected health information
-
Agree to abide by the study schedule and to return for the required assessments
-
Willing and able to comply with the requirements of the protocol
Exclusion Criteria:
-
Detectable FVIII inhibitor at screening, with a titer ≥0.6 Bethesda Unit (BU)
-
Documented history of FVIII inhibitors with a titer ≥0.4 BU at any time prior to screening
-
Known clinical hypersensitivity towards mouse or hamster proteins or to polysialic acid (PSA)
-
Scheduled elective surgery during study participation
-
Severe chronic hepatic dysfunction
-
Severe renal impairment
-
Currently receiving, or has recently received (less than 3 months prior to study participation), or is scheduled to receive during the course of the study, other PSA-ylated drugs
-
Have received another investigational drug within 30 days prior to study entry and/or is scheduled to receive additional investigational drug during the course of the study in the context of another investigational drug study
-
Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A
-
Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug other than antiretroviral chemotherapy
-
Has a clinically significant medical, psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect the safety or compliance of the participant during the study
-
Is a family member or employee of the investigator
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UMHAT "Sv. Georgi", EAD | Plovdiv | Bulgaria | 4000 | |
| 2 | Werlhof-Institut | Hannover | Niedersachsen | Germany | 30159 |
| 3 | Medizinische Hochschule Hannover | Hannover | Niedersachsen | Germany | 30625 |
| 4 | Vivantes Klinikum im Friedrichshain - Landsberger Allee | Berlin | Germany | 10249 | |
| 5 | Universitaetsklinikum des Saarlandes | Homburg | Germany | 66421 | |
| 6 | Universitaetsklinikum Gießen | Marburg | Germany | 35043 | |
| 7 | Semmelweis Egyetem AOK I.sz. Belgyogyaszati Klinika | Budapest | Hungary | 1083 | |
| 8 | Presidio Ospedaliero di Castelfranco Veneto | Castelfranco Veneto | Treviso | Italy | 31033 |
| 9 | Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | Milano | Italy | 20122 | |
| 10 | Policlinico Umberto I di Roma-Università di Roma La Sapienza | Roma | Italy | 00144 | |
| 11 | Radboud University Nijmegen Medical Centre | Nijmegen | Netherlands | 6525 GA | |
| 12 | Erasmus Medisch Centrum | Rotterdam | Netherlands | 3015 AA | |
| 13 | Instytut Hematologii i Transfuzjologii | Warszawa | Poland | 02-776 | |
| 14 | FSBI "Kirov SR Institute of Hematology and Blood Transfusion FMBA" | Kirov | Russian Federation | 610027 | |
| 15 | FSBI "Hematological Research Center" MoH of RF | Moscow | Russian Federation | 125167 | |
| 16 | SBEI HPE "Samara State Medical University" of the MoH of the RF | Samara | Russian Federation | 443099 | |
| 17 | Complejo Hospitalario Universitario A Coruña | A Coruña | La Coruña | Spain | 15006 |
| 18 | Hospital General Universitario de Alicante | Alicante | Spain | 03010 | |
| 19 | Hospital Universitari Vall d'Hebron | Barcelona | Spain | 08035 | |
| 20 | Hospital Universitario La Paz | Madrid | Spain | 28046 | |
| 21 | Hospital Regional Universitario de Malaga | Malaga | Spain | 29010 | |
| 22 | Hospital Universitario Son Espases | Palma de Mallorca | Spain | 07120 | |
| 23 | Royal Cornwall Hospital | Truro | Cornwall | United Kingdom | TR1 3LJ |
| 24 | Royal London Hospital | London | Greater London | United Kingdom | E1 1BB |
| 25 | Royal Free Hospital | London | Greater London | United Kingdom | NW3 2QG |
| 26 | St Thomas' Hospital Centre for Haemostasis & Thrombosis | London | Greater London | United Kingdom | SE1 7EH |
| 27 | Manchester Royal Infirmary | Manchester | Greater Manchester | United Kingdom | M13 9WL |
| 28 | University Hospital of Wales | Cardiff | West Glamorgan | United Kingdom | CF14 4XW |
Sponsors and Collaborators
- Baxalta now part of Shire
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Baxalta now part of Shire
ClinicalTrials.gov Identifier:
NCT02716194
Other Study ID Numbers:
- 291501
- 2015-004079-60
First Posted:
Mar 23, 2016
Last Update Posted:
May 25, 2021
Last Verified:
May 1, 2021
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 20 study sites in the EU and Russia. 44 participants signed informed consent. Of these, 4 participants were not treated (2 screen failures and 2 participants withdrew from study prior to receiving any dosing). |
|---|---|
| Pre-assignment Detail | 44 participants signed informed consent. Of these, 4 participants were not treated (2 screen failures and 2 participants withdrew from study prior to receiving any dosing). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Period Title: Period 1 - ADVATE | |||
| STARTED | 11 | 16 | 13 |
| COMPLETED | 10 | 15 | 13 |
| NOT COMPLETED | 1 | 1 | 0 |
| Period Title: Period 1 - ADVATE | |||
| STARTED | 10 | 15 | 13 |
| COMPLETED | 10 | 15 | 13 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose | Total |
|---|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | Total of all reporting groups |
| Overall Participants | 11 | 16 | 13 | 40 |
| Age (Years) [Median (Full Range) ] | ||||
| Median (Full Range) [Years] |
34.0
|
33.0
|
36.0
|
34.0
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Male |
11
100%
|
16
100%
|
13
100%
|
40
100%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| White |
10
90.9%
|
16
100%
|
13
100%
|
39
97.5%
|
| Other |
1
9.1%
|
0
0%
|
0
0%
|
1
2.5%
|
Outcome Measures
| Title | Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826 |
|---|---|
| Description | Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826. |
| Time Frame | Up to 6 weeks ± 4 days post infusion with BAX826. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in Cohort 1, 2 and 3 in Period 2 (receiving BAX 826) are included. |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 10 | 15 | 13 |
| Any AE |
20
|
12
|
15
|
| Any AE with outcome = Death |
0
|
0
|
0
|
| Any serious AE |
0
|
0
|
0
|
| Any treatment related serious AE |
0
|
0
|
0
|
| Any moderate or severe serious AE |
0
|
0
|
0
|
| Any non-serious AE |
20
|
12
|
15
|
| Any treatment related non-serious AE |
0
|
0
|
0
|
| Any moderate or severe non-serious AE |
8
|
3
|
4
|
| Any systemic AE |
1
|
0
|
4
|
| Any treatment related systemic AE |
0
|
0
|
0
|
| Any moderate or severe systemic AE |
0
|
0
|
1
|
| Any local/non-systemic AE |
19
|
12
|
11
|
| Any treatment related local/non-systemic AE |
0
|
0
|
0
|
| Any moderate or severe local/non-systemic AE |
8
|
3
|
3
|
| Any AE leading to study treatment withdrawal |
0
|
0
|
0
|
| Title | Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments) |
|---|---|
| Description | Clinically significant results after treatment with investigational product that constitute an AE are counted. Vital signs include body temperature, respiratory rate, pulse rate, and blood pressure. Clinical laboratory results include: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (i.e. basophils, eosinophils, lymphocytes, monocytes and neutrophils), international normalized ratio (INR), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count. Clinical Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, glucose. Lipid panel: cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides |
| Time Frame | Screening (Day -30 to -2); Advate Administration (Study Day 1) pre & postdose, and Day 4; Advate washout 96 hours to 4 weeks; BAX826 Administration Day 1 pre & postdose, Post BAX826 Day 4, 8, 14, and 23; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. |
| Measure Participants | 11 | 16 | 13 |
| Clinically significant vital signs |
0
0%
|
0
0%
|
0
0%
|
| Clinically sign. laboratory results after Advate |
0
0%
|
0
0%
|
1
7.7%
|
| Clinically sign. laboratory results after BAX826 |
0
0%
|
0
0%
|
3
23.1%
|
| Title | Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII) |
|---|---|
| Description | Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay. |
| Time Frame | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result. |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 10 | 14 | 13 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826) |
|---|---|
| Description | Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM |
| Time Frame | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result. |
| Arm/Group Title | Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | After the 4 day washout period following the infusion of 25±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 50±5 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 75±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 10 | 14 | 13 | 10 | 15 | 13 |
| IgG: At least 1 positive result (includ.predose) |
1
9.1%
|
0
0%
|
0
0%
|
1
2.5%
|
0
NaN
|
1
NaN
|
| IgG: Predose negative / Postdose positive |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
1
NaN
|
| IgM: At least 1 positive result (includ.predose) |
0
0%
|
1
6.3%
|
0
0%
|
0
0%
|
0
NaN
|
1
NaN
|
| IgM: Predose negative / Postdose positive |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
| Title | Immunogenicity: Binding Antibodies to Factor VIII (FVIII) |
|---|---|
| Description | Binding antibodies to FVIII IgG and IgM |
| Time Frame | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result. |
| Arm/Group Title | Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | After the 4 day washout period following the infusion of 25±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 50±5 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 75±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 14 | 13 | 10 | 15 | 13 |
| IgG: At least 1 positive result (includ.predose) |
0
0%
|
0
0%
|
0
0%
|
1
2.5%
|
0
NaN
|
0
NaN
|
| IgG: Predose negative / Postdose positive |
0
0%
|
0
0%
|
0
0%
|
1
2.5%
|
0
NaN
|
0
NaN
|
| IgM: At least 1 positive result (includ.predose) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
| IgM: Predose negative / Postdose positive |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
| Title | Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies |
|---|---|
| Description | Binding antibodies to PSA (IgG and IgM) |
| Time Frame | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result. |
| Arm/Group Title | Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | After the 4 day washout period following the infusion of 25±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 50±5 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 75±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 14 | 13 | 10 | 15 | 13 |
| IgG: At least 1 positive result (includ.predose) |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
| IgG: Predose negative / Postdose positive |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
| IgM: At least 1 positive result (includ.predose) |
0
0%
|
1
6.3%
|
3
23.1%
|
0
0%
|
1
NaN
|
3
NaN
|
| IgM: Predose negative / Postdose positive |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
NaN
|
0
NaN
|
| Title | Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies |
|---|---|
| Description | Binding antibodies to CHO |
| Time Frame | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The immunogenicity analysis was performed on the participants of the safety population (participants who received at least one administration of BAX 826 or ADVATE) who have a predose and at least one postdose result. |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. |
| Measure Participants | 10 | 15 | 13 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Immunogenicity: Human Anti-murine Antibodies (HAMA) |
|---|---|
| Description | Binding antibodies HAMA (IgG) |
| Time Frame | Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. | The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 10 evaluable participants; Cohort 2: 10 evaluable participants; Cohort 3: 10 evaluable participants]. Participants will be recruited to the next dose level only after short-term safety has been reviewed and subject to approval by a Safety Review Committee at the preceding dose level. |
| Measure Participants | 10 | 15 | 13 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
| Title | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞) |
|---|---|
| Description | Area under the FVIII activity-time curve from zero extrapolated to infinity, calculated by linear-up/log-down trapezoidal method and extrapolated to infinity, calculated as AUC last + C last / lambda z, where Clast is the estimated concentration at the last quantifiable time point |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
901.3
(43.3)
|
1771
(30.9)
|
2496
(39.3)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
1127
(73.1)
|
2363
(24.3)
|
2578
(55.0)
|
| Period 1 (ADVATE) - Chromogenic Assay |
818.9
(38.6)
|
1747
(31.0)
|
2693
(34.9)
|
| Period 2 (BAX 826) - Chromogenic Assay |
1234
(67.4)
|
2742
(36.4)
|
3791
(55.9)
|
| Title | Pharmacokinetics: Terminal Half-life (t1/2) |
|---|---|
| Description | Terminal elimination phase half-life, calculated by (ln2)/lambda z, where lambda z is the terminal rate constant, determined by linear regression of the terminal points of the log-linear FVIII activity-time curve. |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
10.57
(39.1)
|
11.30
(29.6)
|
9.948
(34.8)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
16.18
(41.3)
|
16.90
(21.0)
|
16.22
(28.1)
|
| Period 1 (ADVATE) - Chromogenic Assay |
11.23
(35.4)
|
11.21
(35.7)
|
12.11
(28.5)
|
| Period 2 (BAX826) - Chromogenic Assay |
16.04
(35.6)
|
15.21
(20.2)
|
16.72
(28.2)
|
| Title | Pharmacokinetics: Mean Residence Time (MRT) |
|---|---|
| Description | Mean residence time, calculated as (AUMC 0-∞ / AUC 0-∞) - TI / 2, where TI is the time duration of infusion |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
15.55
(39.9)
|
16.30
(30.5)
|
14.00
(29.7)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
26.96
(43.4)
|
28.90
(17.4)
|
24.33
(27.8)
|
| Period 1 (ADVATE) - Chromogenic Assay |
15.23
(36.1)
|
14.56
(29.5)
|
15.36
(29.1)
|
| Period 2 (BAX826) - Chromogenic Assay |
24.26
(34.1)
|
22.83
(20.3)
|
24.10
(28.2)
|
| Title | Pharmacokinetics: Total Body Clearance (CL) |
|---|---|
| Description | Systemic body clearance of drug from plasma, calculated by dose (IU/kg)/AUC0-∞ |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
0.02803
(47.0)
|
0.02831
(31.4)
|
0.02989
(39.3)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
0.02213
(74.8)
|
0.02161
(25.4)
|
0.02950
(55.8)
|
| Period 1 (ADVATE) - Chromogenic Assay |
0.03085
(42.2)
|
0.02871
(31.5)
|
0.02771
(33.7)
|
| Period 2 (BAX 826) - Chromogenic Assay |
0.02022
(69.4)
|
0.01862
(37.4)
|
0.02006
(57.0)
|
| Title | Pharmacokinetics: Incremental Recovery (IR) |
|---|---|
| Description | Incremental recovery (IR) at Cmax, calculated as IR = (Cmax - Cpreinfusion) / Dose (IU/kg) |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,15,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (9 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 15 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
2.506
(18.1)
|
2.594
(17.0)
|
3.059
(25.3)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
1.544
(27.5)
|
1.560
(22.0)
|
1.641
(41.2)
|
| Period 1 (ADVATE) - Chromogenic Assay |
2.850
(14.6)
|
3.194
(13.0)
|
3.467
(20.4)
|
| Period 2 (BAX826) - Chromogenic Assay |
2.391
(26.4)
|
2.781
(35.2)
|
2.512
(26.2)
|
| Title | Pharmacokinetics: Volume of Distribution at Steady State (Vss) |
|---|---|
| Description | Volume of distribution at steady state is calculated by MRT*CL MRT=Mean residence time CL=Clearance rate |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
0.4359
(17.4)
|
0.4615
(17.7)
|
0.4183
(17.9)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
0.5967
(29.7)
|
0.6246
(24.2)
|
0.7176
(28.4)
|
| Period 1 (ADVATE) - Chromogenic Assay |
0.4700
(14.6)
|
0.4181
(20.6)
|
0.4256
(26.7)
|
| Period 2 (BAX 826) - Chromogenic Assay |
0.4906
(34.6)
|
0.4253
(35.5)
|
0.4835
(32.4)
|
| Title | Pharmacokinetics: Maximum Plasma Concentration (Cmax) |
|---|---|
| Description | Maximum observed FVIII activity, obtained directly from FVIII activity versus time data |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,15,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (9 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 15 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
63.32
(16.4)
|
130.06
(16.4)
|
228.24
(23.5)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
38.53
(26.7)
|
79.65
(21.4)
|
124.78
(40.8)
|
| Period 1 (ADVATE) - Chromogenic Assay |
72.00
(12.8)
|
160.16
(12.1)
|
258.68
(21.4)
|
| Period 2 (BAX826) - Chromogenic Assay |
59.65
(23.8)
|
142.00
(35.1)
|
191.01
(25.7)
|
| Title | Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax) |
|---|---|
| Description | Time of maximum FVIII activity is obtained directly from FVIII activity versus time data |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,15,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (9 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 15 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
0.3000
|
0.3330
|
0.3170
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
0.3000
|
0.5165
|
0.5500
|
| Period 1 (ADVATE) - Chromogenic Assay |
0.3000
|
0.3330
|
0.3085
|
| Period 2 (BAX 826) - Chromogenic Assay |
0.3835
|
0.3165
|
0.3000
|
| Title | Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last) |
|---|---|
| Description | Area under the FVIII activity-time curve from zero to the last quantifiable FVIII activity, calculated by linear-up/log-down trapezoidal method. |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
861.8
(42.5)
|
1712
(30.9)
|
2445
(38.3)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
1078
(73.7)
|
2296
(25.8)
|
2528
(55.9)
|
| Period 1 (ADVATE) - Chromogenic Assay |
785.4
(39.2)
|
1703
(30.3)
|
2625
(34.6)
|
| Period 2 (BAX 826) - Chromogenic Assay |
1181
(70.8)
|
2717
(37.4)
|
3726
(57.2)
|
| Title | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h) |
|---|---|
| Description | AUC from time zero to exactly 72 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 72 hours is missing, the activity at 72 hours will be interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| In period 1 (ADVATE) the number of participants is 11,16,12 respectively for Cohorts 1, 2 and 3. In period 2 (BAX 826) the number of participants is 8, 10 and 11 respectively for cohorts 1, 2 and 3 (10 participants were excluded from the PK analysis for period 2). |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| Period 1 (ADVATE) - One Stage Clotting Assay |
885.9
(41.8)
|
1736
(29.2)
|
2463
(37.5)
|
| Period 2 (BAX 826) - One Stage Clotting Assay |
1041
(68.4)
|
2168
(23.4)
|
2421
(49.7)
|
| Period 1 (ADVATE) - Chromogenic Assay |
803.3
(37.3)
|
1717
(30.0)
|
2638
(34.0)
|
| Period 2 (BAX 826) - Chromogenic Assay |
1157
(63.5)
|
2609
(35.9)
|
3556
(51.5)
|
| Title | Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826 |
|---|---|
| Description | AUC from time zero to exactly 168 hours, calculated by linear-up/log-down trapezoidal method. If the sample at 168 hours is missing, the activity at 168 hours was interpolated or extrapolated using the last quantifiable activity and the terminal rate constant (lambda z). This parameter will be calculated for BAX 826 only. |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 8 | 10 | 11 |
| Period 2 (BAX 826) - One Stage Clotting Assay |
1124
(72.9)
|
2358
(24.2)
|
2572
(54.7)
|
| Period 2 (BAX 826) - Chromogenic Assay |
1231
(67.2)
|
2739
(36.4)
|
3783
(55.6)
|
| Title | Comparison of Key Pharmacokinetic Parameters by Cohort |
|---|---|
| Description | The key pharmacokinetic parameters (Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from 0 to 72 hours (AUC0-72h), Maximum plasma concentration (Cmax), Terminal half-life (t1/2), Mean residence time (MRT) and Total body clearance (CL)) for ADVATE and BAX 826 have been compared. |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Cohort 1 - Low Dose | Cohort 2 - Medium Dose | Cohort 3 - High Dose |
|---|---|---|---|
| Arm/Group Description | Participants were to receive an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 1 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After data from Cohort 2 have been reviewed and approved by an internal Safety Monitoring Committee, participants were to receive an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. Following the washout period, participants were to receive a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. |
| Measure Participants | 11 | 16 | 12 |
| AUC 0-∞: One Stage Clotting Assay |
116.20
|
122.53
|
100.79
|
| AUC 0-∞: Chromogenic Assay |
141.10
|
155.57
|
138.99
|
| AUC 0-72: One Stage Clotting Assay |
109.28
|
115.60
|
96.07
|
| AUC 0-72: Chromogenic Assay |
135.27
|
150.69
|
133.20
|
| Cmax: One Stage Clotting Assay |
61.15
|
63.28
|
54.40
|
| Cmax: Chromogenic Assay |
82.85
|
89.17
|
73.68
|
| t 1/2: One Stage Clotting Assay |
142.10
|
147.44
|
159.52
|
| t 1/2: Chromogenic Assay |
136.97
|
130.84
|
138.28
|
| MRT: One Stage Clotting Assay |
157.83
|
165.99
|
171.33
|
| MRT: Chromogenic Assay |
148.12
|
151.69
|
156.29
|
| CL: One Stage Clotting Assay |
85.97
|
83.21
|
100.98
|
| CL: Chromogenic Assay |
70.73
|
65.44
|
73.26
|
| Title | Summary of Assessment of Dose Proportionality for BAX 826 |
|---|---|
| Description | Dose Proportionality for BAX 826 was calculated for the parameters Area under the concentration-time curve from 0 to infinity (AUC0-∞), Area under the concentration-time curve from time 0 to the last quantifiable time point (AUC0-last) and Maximum plasma concentration (Cmax). |
| Time Frame | Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The PK analysis set consists of all subjects that have received at least 1 administration of ADVATE or BAX 826 and are evaluable for PK for one or both treatments. |
| Arm/Group Title | Pharmacokinetic Analysis Data Set |
|---|---|
| Arm/Group Description | The PK analysis set includes all participants that underwent pharmacokinetic assessments. |
| Measure Participants | 29 |
| AUC 0-∞: One Stage Clotting Assay |
1.668
|
| AUC 0-∞: Chromogenic Assay |
1.979
|
| AUC 0-last: One Stage Clotting Assay |
1.696
|
| AUC 0-last: Chromogenic Assay |
2.014
|
| Cmax: One Stage Clotting Assay |
2.058
|
| Cmax: Chromogenic Assay |
2.055
|
Adverse Events
| Time Frame | Throughout the study period (total study duration approximately 9 months). For each participant from screening until study termination visit (approximately 6 weeks ± 4 days after BAX 826 administration). | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events were recorded throughout the study from screening to completion/termination visit. | |||||||||||
| Arm/Group Title | Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 | ||||||
| Arm/Group Description | Participants received an infusion of 25±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 50±5 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | Participants received an infusion of 75±3 IU/kg ADVATE followed by a minimum 4-day (96 hours) wash out period including a 3 day PK evaluation. | After the 4 day washout period following the infusion of 25±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 50±5 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | After the washout period following the infusion of 75±3 IU/kg ADVATE, participants received a single dose of BAX 826, equivalent to the ADVATE dose they had received, followed by a 7-day PK evaluation. | ||||||
All Cause Mortality |
||||||||||||
| Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
Serious Adverse Events |
||||||||||||
| Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
Other (Not Including Serious) Adverse Events |
||||||||||||
| Cohort 1 - Low Dose ADVATE | Cohort 2 - Medium Dose ADVATE | Cohort 3 - High Dose ADVATE | Cohort 1 - Low Dose BAX 826 | Cohort 2 - Medium Dose BAX 826 | Cohort 3 - High Dose BAX 826 | |||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/11 (27.3%) | 0/16 (0%) | 4/13 (30.8%) | 6/10 (60%) | 6/15 (40%) | 5/13 (38.5%) | ||||||
| Ear and labyrinth disorders | ||||||||||||
| Ear pain | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Eye disorders | ||||||||||||
| Eye pruritus | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/13 (0%) | ||||||
| Gastrointestinal disorders | ||||||||||||
| Abdominal wall haemorrhage | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Diarrhoea | 1/11 (9.1%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Dyspepsia | 0/11 (0%) | 0/16 (0%) | 1/13 (7.7%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
| General disorders | ||||||||||||
| Drug ineffective | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Pyrexia | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Infections and infestations | ||||||||||||
| Hepatitis C | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Nasopharyngitis | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 2/13 (15.4%) | ||||||
| Oral herpes | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 2/13 (15.4%) | ||||||
| Injury, poisoning and procedural complications | ||||||||||||
| Contusion | 0/11 (0%) | 0/16 (0%) | 1/13 (7.7%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Laceration | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Muscle strain | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Traumatic haemorrhage | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Investigations | ||||||||||||
| Alanine aminotransferase increased | 0/11 (0%) | 0/16 (0%) | 1/13 (7.7%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Aspartate aminotransferase increased | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Blood urine present | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/13 (0%) | ||||||
| High density lipoprotein decreased | 0/11 (0%) | 0/16 (0%) | 1/13 (7.7%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||
| Arthralgia | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 1/15 (6.7%) | 1/13 (7.7%) | ||||||
| Back pain | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Haemarthrosis | 1/11 (9.1%) | 0/16 (0%) | 1/13 (7.7%) | 5/10 (50%) | 3/15 (20%) | 0/13 (0%) | ||||||
| Joint range of motion decreased | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/13 (0%) | ||||||
| Joint swelling | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/13 (0%) | ||||||
| Muscle haemorrhage | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Myalgia | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Nervous system disorders | ||||||||||||
| Dizziness | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Headache | 1/11 (9.1%) | 0/16 (0%) | 1/13 (7.7%) | 0/10 (0%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Renal and urinary disorders | ||||||||||||
| Dysuria | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||
| Cough | 0/11 (0%) | 0/16 (0%) | 1/13 (7.7%) | 0/10 (0%) | 0/15 (0%) | 1/13 (7.7%) | ||||||
| Skin and subcutaneous tissue disorders | ||||||||||||
| Erythema | 1/11 (9.1%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
| Vascular disorders | ||||||||||||
| Haematoma | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 0/10 (0%) | 1/15 (6.7%) | 0/13 (0%) | ||||||
| Haemorrhage | 0/11 (0%) | 0/16 (0%) | 0/13 (0%) | 1/10 (10%) | 0/15 (0%) | 0/13 (0%) | ||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication. The sponsor requires a review of results communication (e .g. for confidential information) >= 45 days prior to submission and may request an additional delay of <=210 days (e .g. for intellectual property protection).
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Shire |
| Phone | +1 866 842 5335 |
| ClinicalTransparency@shire.com |
Responsible Party:
Baxalta now part of Shire
ClinicalTrials.gov Identifier:
NCT02716194
Other Study ID Numbers:
- 291501
- 2015-004079-60
First Posted:
Mar 23, 2016
Last Update Posted:
May 25, 2021
Last Verified:
May 1, 2021