Efficacy and Safety of IL-11 in DDAVP Unresponsive

Study Overview
=================
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.

Official Title
-----------------
Phase II Biologic Effects Study of Recombinant Interleukin-11 (rhIL-11, Neumega) in Subjects With Moderate or Mild Hemophilia A, or Von Willebrand Disease Unable to Use DDAVP

Conditions
-----------------
Hemophilia A, Von Willebrand Disease

Intervention / Treatment
-----------------
* Biological: Neumega (Oprelvekin, Interleukin 11, IL-11)


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neumega (Oprelveken, Interleukin 11)<br>Neumega (Oprelveken, interleukin-11 (IL-11) 25 microgram/kilogram by subcutaneou injection once daily for four days, followed on day 4 DDAVP 0.3 microgram/kilogram intravenously 30 minutes after neumega | Biological: Neumega (Oprelvekin, Interleukin 11, IL-11)<br>* 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.<br>* Other names: Oprelvekin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | within 4 days of study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
biologic effects, von Willebrand disease, hemophilia, interleukin-11, DDAVp