Hemophilia A, Von Willebrand Disease
Conditions
Keywords
biologic effects, von Willebrand disease, hemophilia, interleukin-11, DDAVp
Brief summary
The purpose of this study is to determine the biologic efficacy and safety of rhIL-11 when given subcutaneously in adults with moderate or mild hemophilia A or Von Willebrand disease unresponsive to DDAVP. Biologic efficacy will be measured by the number and percent increase of VWD coagulation tests (FVIII:C, VWF: Ag, VWF: RCo, closure time, APTT, and VWF multimers) to the normal range, or at least to 1.5-3 time baseline, following dosing of rhIL-11 when given daily for 4 days, and boosted by DDAVP infusion on day 4, in those in whom DDAVP is not contraindicated. Safety will be measured by the frequency of adverse events, including fever, headache, fatigue, myalgias, arthralgias, fluid retention, or edema.
Detailed description
This is a prospective, single center, Phase II biologic effects study of recombinant interleukin-11 (rhIL-11, Neumega) in subjects hemophilia A, moderate or mild; or with Von Willebrand disease unable to take desmopressin acetate (DDAVP) because they are unresponsive, allergic, or DDAVP is contraindicated. The purpose of the study is to establish the biologic efficacy and safety of rhIL-11 in those not able to take DDAVP. Study subjects will include adults, age \>= 18 years, with hemophilia A, moderate, defined as factor VIII 0.01-0.04 U/ml, or mild, defined as factor VIII \>= 0.05 U/ml; or with VWD defined by low VWF:RCo and /or low VWF:Ag, past bleeding history, and/or family history of VWD. A total of 10-16 subjects will be enrolled in order to assure that 10 complete the study. The specific aims of the study are: 1) to determine the biologic effect of rhIL-11 when given 4 consecutive days; 2) to determine the safety of rhIL-11 when used in subjects with hemophilia A, moderate or mild; or with VWD unresponsive or unable to take DDAVP; and 3) to determine the mechanism of the hemostatic effects of rhIL-11. The biologic efficacy outcomes will be measured by VWD-related coagulation tests (VWF:RCo, FVIII:C, VWF:Ag, closure times) before and after rhIL-11 injection. Safety outcomes will be measured by the number and frequency of adverse events, including fever, headache, fatigue, myalgias, arthralgias, fluid retention, or edema. The mechanism of rhIL-11 hemostatic effect will be measured by VWFmRNA before and after rhIL-11 response. Response to DDAVP following rhIL-11 will also be assessed in those in whom DDAVP is not contraindicated. The study will last up to 1 month per subject, and for 24 months for the entire study.
Interventions
25 microgram/kg IL-11 by subcutaneous injection once daily for four days, followed by DDAVP 0.3 microgram/kg by intravenous infusion over 30 minutes on day 4, 30 minutes after IL-11.
Sponsors
University of Pittsburgh
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
* Males or females \>= 18 years of age. * A diagnosis of hemophilia A, moderate (FVIII:C 0.01-0.04 U/ml) or mild (FVIII:C \>= 0.05 U/ml); or a diagnosis of VWD, defined by a low VWF:RCo and past bleeding history. * For those with VWD, an inability to use DDAVP due to i) unresponsiveness defined as VWF:RCo or FVIII:C level lower than 50 IU/dl or less than a 3-fold increase after 0.3 microgram/kg DDAVP; ii) allergic reactions or seizures; or iii) a contraindication to DDAVP. * Willingness to have blood drawn. * Willingness to sign informed consent.
Exclusion criteria
* Presence of other bleeding disorders, acquired Von Willebrand disease, primary thrombocytopenia. * Use of immunomodulatory or experimental drugs, or diuretics. * Pregnant or lactating women. * Previous cardiac disease, congestive failure, arrhythmia (e.g. atrial fibrillation, atrial flutter), hypertension, MI, stroke, or thrombosis. * Past allergic reaction to Neumega. * Surgery within the past 8 weeks. * Inability to comply with study protocol requirements. * Concomitant use of antiplatelet drugs, anticoagulants, dextran, aspirin or NSAIDs. * Treatment with DDAVP, cryoprecipitate, whole blood, plasma and plasma derivatives containing substantial quantities of FVIII and/or VWF within five days of study. * Baseline safety and/or hematology lab values outside the normal limits and/or an EKG indicating an arrhythmia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biologic Effects by Coagulation Tests | within 4 days of study drug. | VWF activity was measured by ristocetin-induced platelet agglutination using a Chronolog aggregometer11-14 and VWF:Ag by sandwich ELISA, using anti-VWF antibodies (DakoA082, Carpintera CA). Results were expressed in percent, with normal human plasma pool designated 100%, and severe type 3 VWD plasma used as the negative control |
Secondary
| Measure | Time frame |
|---|---|
| The Frequency of Adverse Events | within 11 days of study drug |
| The Mechanism of Study Drug Effect by VWF mRNA. | within 11 days of study drug. |
Countries
United States
Participant flow
Recruitment details
Nine (9) subjects 18 years or older, including five with mild or moderate hemophilia A (HA) and four with mild or moderate von Willebrand disease (VWD) unresponsive or allergic to DDAVP were enrolled in and completed the study between January 2010 and February 2012.
Pre-assignment details
Following enrollment, subjects initiated study drug.
Participants by arm
| Arm | Count |
|---|---|
| Neumega (Oprelveken, Interleukin 11) The VWD subjects included two with type 1 VWD and two with type 2 VWD, including one with type 2B, with increased platelet aggregation at low strength ristocetin and absent high molecular weight multimers, and one with type 2M disease, with reduced VWF:RCoF/ VWF:Ag ratio \<0.50, per NHLBI criteria (Table 2).5 All subjects had positive past bleeding histories. Pregnancy, lactation, heart disease, uncontrolled hypertension, arrhythmia, thrombosis, recent surgery or receipt of blood products were exclusions. A total of nine subjects were enrolled and completed study, including five with hemophilia A and four with VWD. The median age was 26 years, range 22-51 years | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Neumega (Oprelveken, Interleukin 11) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 26 years |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Biologic Effects by Coagulation Tests
VWF activity was measured by ristocetin-induced platelet agglutination using a Chronolog aggregometer11-14 and VWF:Ag by sandwich ELISA, using anti-VWF antibodies (DakoA082, Carpintera CA). Results were expressed in percent, with normal human plasma pool designated 100%, and severe type 3 VWD plasma used as the negative control
Time frame: within 4 days of study drug.
Population: Four subjects had VWD and five subjects had mild hemophilia A
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Neumega (Oprelveken, Interleukin 11) | Biologic Effects by Coagulation Tests | VWD patients | 34.75 percentage of normal | Standard Error 19.2 |
| Neumega (Oprelveken, Interleukin 11) | Biologic Effects by Coagulation Tests | Mild hemophilia A patients | 143.4 percentage of normal | Standard Error 18.6 |
Secondary
The Frequency of Adverse Events
Time frame: within 11 days of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neumega (Oprelveken, Interleukin 11) | The Frequency of Adverse Events | 6 participants |
Secondary
The Mechanism of Study Drug Effect by VWF mRNA.
Time frame: within 11 days of study drug.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Neumega (Oprelveken, Interleukin 11) | The Mechanism of Study Drug Effect by VWF mRNA. | 0.81 fold increase |