Acquired Hemophilia A
Conditions
Keywords
haemophilia A, blood coagulation disorders, coagulation protein disorder, hemophilia A, Acquired Hemophilia A, hematologic diseases, hemorrhagic disorders
Brief summary
This study is to test whether the study drug (OBI-1) is safe and effective for the treatment of serious bleeding episodes in people with acquired hemophilia A.
Interventions
BIOLOGICALOBI-1
Intravenous infusion
Sponsors
Baxalta now part of Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent from subject, trusted person or person who is legally authorized to sign on behalf of the participant (Legal Representative in U.S.), depending on local regulations * Participants with acquired hemophilia with autoimmune inhibitory antibodies to human factor VIII with a clinical diagnosis established by the following criteria: a) Prolonged activated partial thromboplastin time (aPTT), b) Prothrombin time (PT) ≤ upper limit of normal (ULN) + 2 seconds and platelet count within normal range, c) Abnormal aPTT mixing study (patient-normal control 1:1) consistent with a factor VIII inhibitors reduced factor VIII activity level (below 10%) * Has a serious bleeding episode, as documented by the investigator * Be willing and able to follow all instructions and attend all study visits * Participants taking anti-thrombotics (such as clopidogrel, heparin or heparin analogue) may be included provided three half-lives of the agent have elapsed since the last dose of the agent * Life expectancy, prior to onset of the hemorrhagic episode, of at least 90 days * Participants of reproductive age must use acceptable methods of contraception and if female, undergo pregnancy testing as part of the screening process
Exclusion criteria
* Hemodynamically unstable after blood transfusion, fluid resuscitation and pharmacologic or volume replacement pressor therapy. This hemodynamic instability is characterized by symptomatic hypotension resulting in vital organ dysfunction, such as cardiac ischemia, oliguria (urine volume \<0.5 mL/kg in the previous six hours), central nervous system hypoperfusion manifested by mental status change such as confusion (unless head injury or intracranial hemorrhage is present), pulmonary compromise, and/or acidosis (manifested by pH and lactate levels) * Has an established reason for bleeding that is not correctable * Bleeding episode assessed likely to resolve on its own if left untreated * Anti-OBI-1 inhibitor that exceeds 20 Bethesda Units (BU) (prospectively or retrospectively) * Subsequent bleeding episode at the site of the initial qualifying bleeding episode within two weeks following the final OBI-1 dose for the initial qualifying bleeding episode, or subsequent bleeding episode at a different site than the initial qualifying bleeding episode within 1 week following the final OBI-1 dose for the initial qualifying bleeding episode will not be considered new qualifying bleeding episodes * Prior history of bleeding disorder other than acquired hemophilia. * Known major sensitivity to therapeutic products of pig or hamster origin; examples include therapeutics of porcine origin (e.g. previously marketed porcine factor VIII, Hyate-C®) and recombinant therapeutics prepared from hamster cells (e.g. Humira®, Advate® and Enbrel®) * Use of hemophilia medication: rFVIIa within 3 hours prior to OBI-1 administration or aPCC treatment within 6 hours prior to OBI-1 administration * Participation in any other clinical study within 30 days of the first OBI-1 treatment * Anticipated need for treatment or device during the study that may interfere with the evaluation of the safety or efficacy of OBI-1, or whose safety or efficacy may be affected by OBI-1 * Is currently pregnant, breastfeeding, or planning to become pregnant or father a child during the study * Abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject's safety or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study * Inability or unwillingness to comply with the study design, protocol requirements, or the follow-up procedures * Participant of majority age under legal protection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Serious Bleeding Episodes Responsive to OBI-1 | 24 hours after initiation of treatment | The initial serious (qualifying) bleeding episode for each subject was analyzed for the primary efficacy outcome measure. A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Percentage of Serious Bleeding Episodes Successfully Controlled With OBI-1 Therapy, as Assessed by the Investigator | At the time of final treatment dosing (varied from participant to participant depending on bleeding episodes) | Treatment success was defined as control of qualifying bleeding episode at the time of final treatment dosing. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF. |
| PK Analysis- Volume of Distribution (Vd) at Steady State | Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours | Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. |
| Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator | 8 hours | A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'. |
| Frequency of Infusions of OBI-1 Required to Successfully Control Qualifying Bleeding Episodes | Time of successful control of qualifying bleeding episode (varied from participant to participant) | 'Frequency of infusions' was calculated as the 'average number of infusions per day'. 'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. |
| Total Dose of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes | Time of successful control of qualifying bleeding episode (varied from participant to participant) | 'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. |
| Total Number of Infusions of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes | Time of successful control of qualifying bleeding episode (varied from participant to participant) | 'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF. |
| Correlation Between Positive Response to OBI-1 Therapy at 8 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours | 24 hours | — |
| Correlation Between Response to OBI-1 Therapy at Specified Time Points and Eventual Control of Serious Bleeding Episodes at 24 Hours | 24 hours | — |
| Correlation Between the Pre-infusion Anti-OBI-1 Antibody Titers, the Total Dose of OBI-1, the Outcome at 24 Hours and the Eventual Control of the Bleeding Episode | Through 90 days ± 7 days following final OBI-1 dose | — |
| Pharmacokinetics (PK) Analysis- Plasma Clearance | Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours | Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. |
| PK Analysis- Area Under the Concentration-time Curve (AUC) From Time 0 to the Last Measurable Concentration | Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours | Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. AUC was calculated as area under the percent activity-time curve. |
| PK Analysis- Terminal Half-life | Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours | Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. Half-life was calculated as the time it took to reduce percent activity by half. |
| Number of Participants Who Developed de Novo Anti-OBI-1 Antibody Titers | Through 90 days ± 7 days following final OBI-1 dose | — |
| Number of Participants Who Developed an Anti-host Cell Protein Baby Hamster Kidney (BHK) Antibody Titer | Through 90 days ± 7 days following final OBI-1 dose | — |
| Correlation Between Response to OBI-1 Therapy at 16 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours | 24 hours | — |
Other
| Measure | Time frame |
|---|---|
| Anti-human Factor VIII Antibody Titer | Through 90 days ± 7 days following final OBI-1 dose |
Countries
Canada, India, United Kingdom, United States
Participant flow
Recruitment details
Enrollment was conducted at 12 clinical sites in 4 countries (USA, Canada, UK, India). Eight sites enrolled subjects under Protocol OBI-1-301 only. Two US sites enrolled subjects under the expanded access protocol OBI-1-301a and subsequently under protocol OBI-1-301. Another 2 US sites enrolled subjects under OBI-1-301a only.
Pre-assignment details
29 subjects were enrolled and all were treated with OBI-1. Data from the expanded access subjects (Protocol 301a, n= 4) are included with the data from subjects enrolled under Protocol OBI-1-301 (n=25). 10 subjects discontinued prematurely and 18 completed the study. For one subject, the completion status could not be verified.
Participants by arm
| Arm | Count |
|---|---|
| OBI-1 Initial dose: 200 U/kg - additional doses at the discretion of the investigator based on FVIII activity level and clinical assessment of response to treatment (upper limit: 400 U/kg every 2 hours) | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Completion status could not be verified | 1 |
| Overall Study | Death | 1 |
| Overall Study | Development of inhibitors to OBI-1 | 1 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Subject status is terminal | 1 |
Baseline characteristics
| Characteristic | OBI-1 |
|---|---|
| Age, Continuous | 69.8 years STANDARD_DEVIATION 13.28 |
| Region of Enrollment Canada | 5 Participants |
| Region of Enrollment India | 4 Participants |
| Region of Enrollment United Kingdom | 4 Participants |
| Region of Enrollment United States | 16 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 27 / 29 |
| serious Total, serious adverse events | 13 / 29 |
Outcome results
Primary
Percentage of Serious Bleeding Episodes Responsive to OBI-1
The initial serious (qualifying) bleeding episode for each subject was analyzed for the primary efficacy outcome measure. A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.
Time frame: 24 hours after initiation of treatment
Population: Intent to Treat (ITT) population = 29 subjects with initial serious bleeding episodes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Percentage of Serious Bleeding Episodes Responsive to OBI-1 | 100 percentage of serious bleeding episodes |
Comparison: Summary statistics for the percentage of participants with serious bleeding episodes responsive at 24 hours after the initiation of treatment are presented, along with the 95% confidence interval (two-sided 95% Clopper-Pearson confidence interval).p-value: <0.001one-sided binomial exact test
Secondary
Correlation Between Positive Response to OBI-1 Therapy at 8 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours
Time frame: 24 hours
Population: Of 21 subjects in the ITT population (n=29) with responses available at 8 hours after initial infusion of OBI-1, 20 had a positive response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Correlation Between Positive Response to OBI-1 Therapy at 8 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours | 17 subjects with eventual bleed control |
Secondary
Correlation Between Response to OBI-1 Therapy at 16 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours
Time frame: 24 hours
Population: All 19 subjects in the ITT population (n=29) who had responses available at 16 hours after initial infusion of OBI-1 had a positive response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Correlation Between Response to OBI-1 Therapy at 16 Hours and Eventual Control of Serious Bleeding Episodes at 24 Hours | 17 subjects with eventual bleed control |
Secondary
Correlation Between Response to OBI-1 Therapy at Specified Time Points and Eventual Control of Serious Bleeding Episodes at 24 Hours
Time frame: 24 hours
Population: 29 subjects (ITT population) had responses available at 24 hours after initial infusion of OBI-1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Correlation Between Response to OBI-1 Therapy at Specified Time Points and Eventual Control of Serious Bleeding Episodes at 24 Hours | 25 participants with bleeds controlled |
Secondary
Correlation Between the Pre-infusion Anti-OBI-1 Antibody Titers, the Total Dose of OBI-1, the Outcome at 24 Hours and the Eventual Control of the Bleeding Episode
Time frame: Through 90 days ± 7 days following final OBI-1 dose
Population: Because of expected sparseness of positive anti-OBI-1 antibody titers, formal statistical analyses of correlation were not performed.
Secondary
Frequency of Infusions of OBI-1 Required to Successfully Control Qualifying Bleeding Episodes
'Frequency of infusions' was calculated as the 'average number of infusions per day'. 'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'.
Time frame: Time of successful control of qualifying bleeding episode (varied from participant to participant)
Population: The analysis was performed in 25 of 29 participants in the ITT population whose 'qualifying' bleeding episode was controlled successfully.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OBI-1 | Frequency of Infusions of OBI-1 Required to Successfully Control Qualifying Bleeding Episodes | 2.10 average number of infusions per day | Standard Deviation 1.109 |
Secondary
Number of Participants Who Developed an Anti-host Cell Protein Baby Hamster Kidney (BHK) Antibody Titer
Time frame: Through 90 days ± 7 days following final OBI-1 dose
Population: 21 subjects in the ITT population (n=29) with available baseline and follow-up test results
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Number of Participants Who Developed an Anti-host Cell Protein Baby Hamster Kidney (BHK) Antibody Titer | 0 participants |
Secondary
Number of Participants Who Developed de Novo Anti-OBI-1 Antibody Titers
Time frame: Through 90 days ± 7 days following final OBI-1 dose
Population: 28 eligible subjects with acquired hemophilia A in the ITT population (n=29), of whom 18 had no detectable anti-porcine FVIII inhibitor titers at baseline (\<0.6 BU) and 10 had detectable anti-porcine FVIII antibody titers at baseline (\>=0.6 BU)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Number of Participants Who Developed de Novo Anti-OBI-1 Antibody Titers | 5 participants |
Secondary
Overall Percentage of Serious Bleeding Episodes Successfully Controlled With OBI-1 Therapy, as Assessed by the Investigator
Treatment success was defined as control of qualifying bleeding episode at the time of final treatment dosing. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF.
Time frame: At the time of final treatment dosing (varied from participant to participant depending on bleeding episodes)
Population: ITT population = 29 subjects with initial serious bleeding episodes (BEs)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Overall Percentage of Serious Bleeding Episodes Successfully Controlled With OBI-1 Therapy, as Assessed by the Investigator | 86.2 percentage of serious bleeding episodes |
Secondary
Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator
A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.
Time frame: 16 hours
Population: 19 subjects of the ITT population (n=29) had responses available at 16 hours after initial infusion of OBI-1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator | 100 percentage of serious bleeding episodes |
Secondary
Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator
A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.
Time frame: 8 hours
Population: 21 subjects of the ITT population (n=29) had responses available at 8 hours after initial infusion of OBI-1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OBI-1 | Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator | 95.2 percentage of serious bleeding episodes |
Secondary
Pharmacokinetics (PK) Analysis- Plasma Clearance
Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics.
Time frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours
Population: PK population (= all subjects in the ITT population who consent to PK draws and have factor VIII levels measured at the central reference laboratory)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OBI-1 | Pharmacokinetics (PK) Analysis- Plasma Clearance | Chromogenic FVIII activity assay | 11.80 U/(percent activity*hours) | Standard Deviation 13.44 |
| OBI-1 | Pharmacokinetics (PK) Analysis- Plasma Clearance | One-stage FVIII activity assay | 18.07 U/(percent activity*hours) | Standard Deviation 21.78 |
Secondary
PK Analysis- Area Under the Concentration-time Curve (AUC) From Time 0 to the Last Measurable Concentration
Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. AUC was calculated as area under the percent activity-time curve.
Time frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OBI-1 | PK Analysis- Area Under the Concentration-time Curve (AUC) From Time 0 to the Last Measurable Concentration | Chromogenic FVIII activity assay | 599 percent activity*hours | Standard Deviation 459 |
| OBI-1 | PK Analysis- Area Under the Concentration-time Curve (AUC) From Time 0 to the Last Measurable Concentration | One-stage FVIII activity assay | 423 percent activity*hours | Standard Deviation 340 |
Secondary
PK Analysis- Terminal Half-life
Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. Half-life was calculated as the time it took to reduce percent activity by half.
Time frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OBI-1 | PK Analysis- Terminal Half-life | Chromogenic FVIII activity assay | 3.3 hours | Standard Deviation 0.4 |
| OBI-1 | PK Analysis- Terminal Half-life | One-stage FVIII activity assay | 3.5 hours | Standard Deviation 1 |
Secondary
PK Analysis- Volume of Distribution (Vd) at Steady State
Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics.
Time frame: Pre-infusion 15-20 minutes, Post-infusion 1, 3, 6, 12, 18, 24 hours
Population: PK population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OBI-1 | PK Analysis- Volume of Distribution (Vd) at Steady State | Chromogenic FVIII activity assay | 53.8 U/percent activity | Standard Deviation 52.9 |
| OBI-1 | PK Analysis- Volume of Distribution (Vd) at Steady State | One-stage FVIII activity assay | 65.1 U/percent activity | Standard Deviation 45.1 |
Secondary
Total Dose of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes
'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'.
Time frame: Time of successful control of qualifying bleeding episode (varied from participant to participant)
Population: The analysis was performed in 25 of 29 participants in the ITT population whose 'qualifying' bleeding episode was controlled successfully.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OBI-1 | Total Dose of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes | 2683.2 dose in U/kg | Standard Deviation 2928.61 |
Secondary
Total Number of Infusions of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes
'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF.
Time frame: Time of successful control of qualifying bleeding episode (varied from participant to participant)
Population: The analysis was performed in 25 of 29 participants in the ITT population whose 'qualifying' bleeding episode was controlled successfully.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OBI-1 | Total Number of Infusions of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes | 15.4 infusions per participant | Standard Deviation 12.64 |
Other Pre-specified
Anti-human Factor VIII Antibody Titer
Time frame: Through 90 days ± 7 days following final OBI-1 dose
Population: Anti-human factor VIII antibody titer data were presented in subject data listings. No statistical test was planned for anti-human factor VIII antibody titer.