Hemophilia A With Inhibitor
Conditions
Keywords
hemophilia, inhibitor formation, Eloctate, Emicizumab
Brief summary
This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in severe hemophilia A.
Detailed description
This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in patients with severe hemophilia A This adaptive design is necessary as randomized trials in rare diseases are often not possible. The INHIBIT Clinical Trials Platform includes two linked trials, the Inhibitor Prevention Trial (Prevention Trial) and the Inhibitor Eradication Trial (Eradication Trial) that will be conducted at up to 41 U.S. hemophilia treatment centers (HTCs) affiliated with universities. The Inhibitor Eradication Trial is a 48-week randomized phase III trial, in which 90 previously treated patients (PTPs) with severe hemophilia A and high-responding inhibitors (anti-VIII \> 0.6 B.U.), will be enrolled. Subjects will include individuals with severe hemophilia A who develop inhibitors during the linked Inhibitor Prevention Trial and adults or children at the same HTCs refractory to or never undergoing immune tolerance induction (ITI). Once enrolled, subjects who meet all the inclusion and none of the exclusion criteria, will be randomized to weekly Eloctate ITI plus weekly Emicizumab vs. weekly Eloctate ITI alone to eradicate inhibitor formation, defined as anti-FVIII\<0.6 B.U. Blood draws will be minimized to 6 timepoints, pre, 4, 12, 24, 36, and 48 weeks, and validated for small volumes, 3.8 cc (¾ tsp) each. The Inhibitor Eradication Trial is considered greater than minimal risk as study drug is given before the first bleed and special inhibitor studies are obtained. (NB: The Inhibitor Eradication Trial (PRO19070080) is linked to the Inhibitor Prevention Trial (PRO19040140), as part of the INHIBIT Clinical Trials Platform, and both trials will be conducted efficiently in the same hemophilia treatment centers (HTCs), with the same MDs, coordinators, visit frequency, blood sampling, and assays.
Interventions
DRUGEloctate ITI
This is a factor VIII-Fc infusion protein.
DRUGEmicizumab
This is a bispecific monoclonal antibody FVIII mimic.
Sponsors
Health Resources and Services Administration (HRSA)
Margaret Ragni
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a phase III open-label, randomized controlled trial comparing immune tolerance induction with one drug, with or without a second drug in the eradication of hemophilia inhibitors.
Eligibility
Sex/Gender
MALE
Healthy volunteers
No
Inclusion criteria
1. Male adults or children \> 4 months of age. 2. Severe hemophilia A (FVIII \< 0.01 U/ml). 3. Current or past high-responding inhibitor, anti-FVIII \>= 5.0 B.U., ITI-refractory or ITI-naive.
Exclusion criteria
1. Acquired hemophilia or any bleeding disorder other than hemophilia A. 2. Current use of Emicizumab, or if used, \> 8 weeks since last treatment. 3. Use of an experimental drug(s). 4. Surgery anticipated in the next 48 weeks. 5. Life expectancy less than 5 years. 6. Patient/parent/caretaker unable or unwilling to keep a personal diary of bleeding frequency and study drug treatment, make monthly visits and blood draws at weeks 4, 8, 12, 24, 36, and 48. 7. Other illness, condition, or reason in the opinion of the investigator that would make the patient unsuitable for the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Inhibitor Eradication | 48 weeks | The proportion eradicating anti-FVIII inhibitors |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeding Events | 48 weeks | The number of bleeding events: hematoma, joint, central nervous system, other bleeds. |
| FVIII Trough Level | 48 weeks | The FVIII trough activity by chromogenic assay. |
| Human Leukocyte Antigen (HLA) Haplotype | 48 weeks | The number of HLA haplotype variants. |
| FVIII Mutation | 48 weeks | The number of FVIII mutation variants. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eloctate ITI Eloctate 100 IU/kg every other day by intravenous infusion in children and adults with severe hemophilia A and anti-FVIII inhibitor, continued up to 48 weeks.
Eloctate ITI: This is a factor VIII-Fc infusion protein. | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Study closed due to poor enrollment | 1 |
Baseline characteristics
| Characteristic | Eloctate ITI |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 1 years |
| Anti-FVIII level > 0.6 BU | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Number and Type of Bleeds in the last year | 0 Bleeds |
| Prior Circumcision | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Inhibitor Eradication
The proportion eradicating anti-FVIII inhibitors
Time frame: 48 weeks
Population: Only patient was enrolled on study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Eloctate ITI | Inhibitor Eradication | 1 Participants |
Secondary
FVIII Mutation
The number of FVIII mutation variants.
Time frame: 48 weeks
Population: specimen collected, discarded with out analysis due to study being close dearly due to low enrollment
Secondary
FVIII Trough Level
The FVIII trough activity by chromogenic assay.
Time frame: 48 weeks
Population: specimen collected, discarded with out analysis due to study being close dearly due to low enrollment
Secondary
Human Leukocyte Antigen (HLA) Haplotype
The number of HLA haplotype variants.
Time frame: 48 weeks
Population: specimen collected, discarded with out analysis due to study being close dearly due to low enrollment
Secondary
Number of Bleeding Events
The number of bleeding events: hematoma, joint, central nervous system, other bleeds.
Time frame: 48 weeks
Population: Only patient was enrolled on study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eloctate ITI | Number of Bleeding Events | 0 number of bleeding events |