Bleeding, Thrombocytopenia, Wiskott-Aldrich Syndrome
Conditions
Brief summary
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
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.
Interventions
DRUGPromacta
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
DIAGNOSTIC_TESTblood drawing in patients with WAS
blood will be drawn for platelet parameters in WAS patients not receiving treatment either because they declined or because they were ineligible
DIAGNOSTIC_TESTblood drawing in healthy controls
blood will be drawn once in healthy children as controls for platelet parameters
Sponsors
Novartis Pharmaceuticals
Weill Medical College of Cornell University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
1. group of 11 WAS patients treated with eltrombopag 2. WAS patients who had their blood drawn once but did not receive eltrombopag treatment 3. healthy children as controls for testing only 3\) healthy volunteers who had their blood drawn once
Eligibility
Sex/Gender
MALE
Age
3 Months to 80 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| How Many WAS Patients Will Achieve Platelet Counts Above 50,000/ul. | 12 weeks | number of WAS patients achieving this increase to \> 50,000/uL without rescue medication in the previous 3 weeks during eltrombopag treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Wiskott-Aldrich Syndrome (WAS) With Grade 3 or Higher Bleeding or SAE (on WHO Scale) | 12 Weeks | 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 |
| How Many Patients With WAS Had Abnormal Platelet Function Including Activation | 12 weeks | 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 |
| How Many Patients With WAS Had Substantially Increased Platelet Production After Eltrombopag | 12 weeks | 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 |
Countries
United States
Participant flow
Recruitment details
24 patients' families signed consents 11 WAS patients for treatment: 1 mother signed consent but never consented to have her very young baby start study treatment (dietary issues) + 1 withdrew 8 WAS patients' parents only were willing to have study bloods drawn 5 normal healthy children had their parents give consent for a blood draw
Participants by arm
| Arm | Count |
|---|---|
| Promacta 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.
Promacta (eltrombopag): Patients 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.
Eltrombopag/promacta: Patients 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. | 11 |
| Healthy Volunteers 5 well children having blood drawn for another reason: 3 pre-op and 2 for HLAA-typing | 5 |
| WAS Patients for Blood Drawing Only patients with WAS either not eligible or not interested in eltrombpopag treatment who are willing to have their blood drawn once | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Healthy Volunteers | WAS Patients for Blood Drawing Only | Promacta |
|---|---|---|---|---|
| Age, Categorical <=18 years | 23 Participants | 5 Participants | 8 Participants | 10 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — |
| Region of Enrollment United States | 24 participants | 5 participants | 8 participants | 11 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 22 Participants | 3 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 5 | 0 / 8 |
| other Total, other adverse events | 2 / 10 | 0 / 5 | 0 / 8 |
| serious Total, serious adverse events | 3 / 10 | 0 / 5 | 0 / 8 |
Outcome results
Primary
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
Time frame: 12 weeks
Population: 1 WAS subject withdrew prior to starting treatment and was not included in the analysis.~Healthy volunteers were neither WAS patients nor received eltrombopag (both required for achievement of primary outcome #1). The WAS patients who were blood draw only also were 0 since they did not receive eltrombopag.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Promacta | How Many WAS Patients Will Achieve Platelet Counts Above 50,000/ul. | 8 participants |
Secondary
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
Time frame: 12 weeks
Population: 1 subject withdrew prior to starting treatment and was not included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Promacta | How Many Patients With WAS Had Abnormal Platelet Function Including Activation | 0 participants |
| Healthy Volunteers | How Many Patients With WAS Had Abnormal Platelet Function Including Activation | 0 participants |
| Was Patients Blood Drawing Only | How Many Patients With WAS Had Abnormal Platelet Function Including Activation | 0 participants |
Secondary
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
Time frame: 12 weeks
Population: 1 subject withdrew prior to starting treatment and was not included in the analysis. no treatment with eltrombopag was given to healthy volunteers and WAS patients who were blood drawing only so the effect of treatment in these 2 groups could not be assessed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Promacta | How Many Patients With WAS Had Substantially Increased Platelet Production After Eltrombopag | 3 Participants |
| Healthy Volunteers | How Many Patients With WAS Had Substantially Increased Platelet Production After Eltrombopag | 0 Participants |
| Was Patients Blood Drawing Only | How Many Patients With WAS Had Substantially Increased Platelet Production After Eltrombopag | 0 Participants |
Secondary
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
Time frame: 12 Weeks
Population: 1 subject withdrew prior to starting treatment and was not included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Promacta | Number of Patients With Wiskott-Aldrich Syndrome (WAS) With Grade 3 or Higher Bleeding or SAE (on WHO Scale) | 1 participants |
| Healthy Volunteers | Number of Patients With Wiskott-Aldrich Syndrome (WAS) With Grade 3 or Higher Bleeding or SAE (on WHO Scale) | 0 participants |
| Was Patients Blood Drawing Only | Number of Patients With Wiskott-Aldrich Syndrome (WAS) With Grade 3 or Higher Bleeding or SAE (on WHO Scale) | 0 participants |