Severe Hemophilia A
Conditions
Keywords
Hemophilia, Prophylaxis, Recombinant factor VIII
Brief summary
The purpose of this pilot R34 trial is to determine the feasibility of a large single dose Phase III study of hemophilia adult prophylaxis comparing once weekly with thrice-weekly recombinant factor VIII. Efficacy will measured by bleeding frequency, factor usage, joint range of motion, cost, quality-of-life, F.VIII level, and inter-dose hypocoagulability by thrombin generation. Safety will be measured by inhibitor formation and bleeding events unresponsive to up to two rescue doses.
Detailed description
The purpose of this 52-week pilot R34 randomized, open-label, non-inferiority, cross-over study is to determine the feasibility of a large single dose Phase III study of hemophilia adult prophylaxis. The primary efficacy endpoint will be bleeding frequency. Secondary endpoints will include factor usage, joint range of motion, cost, quality-of-life, and inter-dose hypocoagulability by thrombin generation time and F.VIII activity will also be determined. Safety will be measured by the frequency of bleeding unresponsive to up to two rescue treatments. Inhibitor formation by anti-F.VIII Bethesda assay, and clinical frequency of thrombosis and allergic reactions will also be assessed. Subject acceptance and adherence to the treatment interventions will be determined; and web-based data entry of case report forms, digital range-of-motion images, and quality-of-life instrument will be implemented. The relation of bleeding frequency to relative inter-dose hypocoagulability, will be assessed by inter-dose thrombin generation time (TGT), endogenous thrombin potential (ETP), and factor VIII levels. Optimal blood sample collection and shipping methods will be determined. For all tests, we will estimate and determine completeness and congruency, in order to determine adjustments or revisions required before initiating a large phase III Randomized clinical trial. All testing will be exploratory, so that we may determine if the test, approach are realistic, and to estimate standard deviations for future power analyses.
Interventions
DRUGrF.VIII
40 IU/kg recombinant factor VIII will be given once-weekly or thrice-weekly by intravenous injection for 26 weeks. At 26 weeks after a 72 hour washout period, 40 IU/kg recombinant factor VIII will be given thrice-weekly or once-weekly, respectively, by intravenous injection until week 52, with up to two rescue doses per week for bleeds
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult males 18 years or older * Severe hemophilia A (F.VIII \< 0.01 U/ml) * At least 150 exposure days to F.VIII products * No detectable inhibitor * No history of allergic reaction * Platelets at least 150,000/ul * If HIV(+), CD4 at least 200/ul, HIV-VL \<48 copies/ml,and cART compliant * If HCV(+), no splenomegaly,varices,GI bleed,ascites,edema,encephalopathy * Willingness to comply with cross-over design, randomization schema * Willingness to keep a personal diary of bleeding frequency and factor use * Willingness to make every 3 month visits, coagulation testing at wks 2, 28
Exclusion criteria
* Acquired hemophilia * Any bleeding disorder other than hemophilia A * Presence of an inhibitor to factor VIII * Historic platelet count \< 100,000 * Use of experimental drugs * Surgery anticipate in the next 52 weeks * Symptomatic HCV(splenomegaly,varices,GI bleed,ascites,edema,encephalopathy) * Symptomatic HIV(CD4\<200/ul or HIV VL 48 or more copy/ml,cART noncompliant) * Life expectancy less than 5 years * Investigational drug or study within 4 weeks prior to study * Inability to comply with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeds | Weeks 26 (first intervention) and 52 (second intervention) | The primary outcome was bleed frequency. The data were total number of events for each Arm, and not per-participant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| F.VIII Activity | The time frame is 52 weeks per subject. | F.VIII Activity (IU/mL) performed at week 8 and week 34, i.e. 8 weeks after initiation of factor dosing in Weeks 1-26, and 8 weeks after initiation of factor dosing in Weeks 27-52. |
| Inter-dose Hypocoagulability by Thrombin Generation | The time frame is 52 weeks per subject. | Thrombin generation was performed at week 8 and week 34, i.e. 8 weeks after initiation of factor dosing in Weeks 1-26, and 8 weeks after initiation of factor dosing in Weeks 27-52. |
Countries
United States
Participant flow
Pre-assignment details
Following enrollment, subjects initiated study drug according to the randomization to Arm A (once-weekly FVIII) or Arm B (thrice-weekly FVIII) for a 26 week period followed by a 72 hour washout period prior to crossover to the other arm for the second 26 week period.
Participants by arm
| Arm | Count |
|---|---|
| Severe Hemophilia A Subjects will be randomized to receive either once-weekly F.VIII at 40 IU/kg (Arm A) or thrice-weekly F.VIII at 40 IU/kg (Arm B) for the first 26 weeks of study. Then, at 26 weeks, they will undergo Cross-Over, that is, switch to the alternative Study Arm for the last 26 weeks, following a 72 hour washout period. | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Severe Hemophilia A |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 25.5 year |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Number of Bleeds
The primary outcome was bleed frequency. The data were total number of events for each Arm, and not per-participant.
Time frame: Weeks 26 (first intervention) and 52 (second intervention)
Population: 3 completing study were analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Once Weekly FVIII | Number of Bleeds | 3 bleeds per 26 weeks |
| Thrice Weekly FVIII | Number of Bleeds | 16 bleeds per 26 weeks |
Secondary
F.VIII Activity
F.VIII Activity (IU/mL) performed at week 8 and week 34, i.e. 8 weeks after initiation of factor dosing in Weeks 1-26, and 8 weeks after initiation of factor dosing in Weeks 27-52.
Time frame: The time frame is 52 weeks per subject.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Once Weekly FVIII | F.VIII Activity | 1.04 IU/mL |
| Thrice Weekly FVIII | F.VIII Activity | 0.90 IU/mL |
Secondary
Inter-dose Hypocoagulability by Thrombin Generation
Thrombin generation was performed at week 8 and week 34, i.e. 8 weeks after initiation of factor dosing in Weeks 1-26, and 8 weeks after initiation of factor dosing in Weeks 27-52.
Time frame: The time frame is 52 weeks per subject.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Once Weekly FVIII | Inter-dose Hypocoagulability by Thrombin Generation | 110.65 nMs |
| Thrice Weekly FVIII | Inter-dose Hypocoagulability by Thrombin Generation | 82.86 nMs |