Thrombocytopenia and Bleeding in Wiskott-Aldrich Syndrome (WAS) Patients

Study Overview
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Brief Summary
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The purpose of this project is to describe the pathophysiology of thrombocytopenia and bleeding in patients with Wiskott-Aldrich Syndrome (WAS) and determine the response to thrombopoietic agents in vitro and in vivo.

Detailed Description
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Wiskott Aldrich Syndrome is an X-linked disease characterized by immunodeficiency, eczema and thrombocytopenia; a milder form of the disease known as X-Linked thrombocytopenia also exists. The thrombocytopenia in both WAS and XLT is characterized by: severe thrombocytopenia with platelet counts frequently less than 10-30,000/ul; small platelets which may be dysfunctional; and, as a result, a high rate of serious bleeding including intracranial hemorrhage. Because eltrombopag has been shown to be remarkably efficacious in substantially increasing platelet counts in a high percentage of ITP patients, this study seeks to effectively treat patients who exhibit similar pathologies, as well as evaluate the state of platelets in patients with WAS and relate it to clinical bleeding. It also aims to demonstrate whether eltrombopag administered daily will enhance stem cell function, increase platelet production and platelet count, and reduce bleeding in patients with WAS.

Official Title
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Effects Of Eltrombopag On Thrombocytopenia, Platelet Function and Bleeding In Patients With Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia.

Conditions
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Wiskott-Aldrich Syndrome, Thrombocytopenia, Bleeding

Intervention / Treatment
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* Drug: Promacta
* Diagnostic Test: blood drawing in patients with WAS
* Diagnostic Test: blood drawing in healthy controls


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible for study entry, subjects must comply with the following: Males from 3 months old to 80 years old Signed written informed consent obtained prior to study entry Clinical diagnosis of WAS or XLT Platelet levels less than 100 x 109/L Adequate renal and hepatic function (creatinine and bilirubin less than or equal to 1.5 x IULN, AST and ALT less than or equal to 2.5 x IULN) Exclusion Criteria: Any patient is ineligible for study entry if he/she: Over the age of 80 Women (only males are eligible) fertile men who are not practicing or who are unwilling to practice birth control while enrolled in the study or until at least 6 months after treatment Aspirin, aspirin-containing compounds, salicylates, non-steroidal anti-inflammatory medications (NSAIDS), clopidogrel or ticlopidine, warfarin or other vitamin K antagonists, unfractionated or low molecular heparin within 7 days of first infusion Red blood cell transfusion in the past four weeks Elevated (> 1.5 x ULN) prothrombin time (PT) or partial thromboplastin time (PTT) New York Heart Classification III or IV heart disease. Other severe cardiovascular or cardiopulmonary disease, including COPD. Known HIV infection, hepatitis B or C infection Any infection requiring antibiotic treatment within 3 days Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations. Prior malignancy with less than a 5-year disease-free interval, excluding nonmelanoma skin cancers and carcinoma in situ of the cervix

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: group of 11 WAS patients treated with eltrombopag WAS patients who had their blood drawn once but did not receive eltrombopag treatment healthy children as controls for testing only 3) healthy volunteers who had their blood drawn once
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WAS patients receiving Promacta<br>Promacta® is commercially available in 12.5 mg, 25 mg, 50 mg, and 75 mg tablets. For this study, for young children unable to swallow a tablet, eltrombopag powder for oral suspension (Eltrombopag PfOS) will be used. PfOS is only available for investigational use at 20mg. Each sachet contains eltrombopag equivalent to 20mg per gm of powder and is reconstituted to a total of 10 ml so that the concentration is 2 mg/ml. | Drug: Promacta<br>* WAS Patients receiving treatment will start on 1 mg/kg of eltrombopag daily and be seen weekly for 12 weeks. Dose adjustment will be based on the weekly monitoring of the platelet count as utilized in ongoing studies in ITP as well as on liver tests. they will also have diagnostic blood testing prior to initiating treatment<br>* Other names: eltrombopag, revolade;|
| Experimental: WAS patients for blood drawing only<br>WAS patients not receiving treatment to serve as subjects for platelet parameter studies blood drawing once only | Diagnostic Test: blood drawing in patients with WAS<br>* blood will be drawn for platelet parameters in WAS patients not receiving treatment either because they declined or because they were ineligible<br>|
| Placebo Comparator: healthy children for blood drawing only<br>healthy children having blood obtained once as controls for platelet parameters study | Diagnostic Test: blood drawing in healthy controls<br>* blood will be drawn once in healthy children as controls for platelet parameters<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| How Many WAS Patients Will Achieve Platelet Counts Above 50,000/ul. | number of WAS patients achieving this increase to > 50,000/uL without rescue medication in the previous 3 weeks during eltrombopag treatment | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Wiskott-Aldrich Syndrome (WAS) With Grade 3 or Higher Bleeding or SAE (on WHO Scale) | number of patients with bleeding SAEs while on treatment and/or number of patients with grade 3 or higher bleeding on WHO (World Health Organization) scale: the scale is from 1 to 5 with 5 = fatality and 1=very little bleeding | 12 Weeks | 
| How Many Patients With WAS Had Abnormal Platelet Function Including Activation | in how many patients with WAS were platelets dysfunctional or activated before treatment as measured by flow cytometry to a substantial degree and the same after treatment with eltrombopag | 12 weeks | 
| How Many Patients With WAS Had Substantially Increased Platelet Production After Eltrombopag | in how many patients with WAS did eltrombopag increase platelet production as measured by the immature platelet fraction (IPF), a variable derived from the Sysmex auto analyzer, which is considered to be a measure of newly formed platelets ie reticulated platelets | 12 weeks |