Efficacy and Safety of Romiplostim Versus Eltrombopag in the Treatment of Thrombocytopenia in Patients With Wiskott-Aldrich Syndrome

Study Overview
=================
Brief Summary
-----------------
This is a prospective, open-label, randomized, two-arm clinical trial conducted to evaluate the safety and efficacy of romiplostim in comparison with eltrombopag in the treatment of thrombocytopenia in patients with Wiskott-Aldrich syndrome

Detailed Description
-----------------
Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to severe thrombocytopenia. Considering that the hemorrhagic events are a cause of death in 21% of WAS patients, management of thrombocytopenia constitutes a major challenge. Findings of defective platelet production by megakaryocytes and reduced in vitro pro-platelet formation suggested the possibility of megakaryocyte stimulation by TPO-RAs romiplostim, eltrombopag as a treatment strategy. Each of them has distinct pharmacodynamic, pharmacokinetic properties, different effects on megakaryopoiesis, and might have different efficacy in individual patients. The aim of this study is to compare the efficacy and safety of romiplostim and another TPO-RA eltrombopag for the treatment of thrombocytopenia in patients with WAS and assess the benefit of switching these molecules in refractory subjects. The patients will be randomized in a 1:1 fashion to receive either romiplostim or eltrombopag. After enrollment, (see detailed inclusion and exclusion criteria below) subjects under 18 years of age with a confirmed diagnosis of WAS and thrombocytopenia (platelet count of less than 70 x 109/L) will be assigned to receive romiplostim at an initial dose of 9 µg/kg subcutaneously per week or oral eltrombopag at a dose of 2-3mg/kg daily (ages 1 to 5 years) and 75 mg/daily (>6 years) for at least 1 month. Bleeding severity will be evaluated with a modified World Health Organization (WHO) Bleeding Scale, lab tests (blood counts, biochemical analyses), ECG will be assessed after 30 days of treatment (30 +/- 7 days). The efficacy of romiplostim/eltrombopag will be defined by the following criteria: complete response -an achievement of the platelet count >100 x 109/L, partial - platelet count at least 30 x 109/L higher than the patient's pretreatment baseline count up to to 100 x 109/L. No response will be defined as not achieving a platelet count of > 30 x 109/L from the baseline count. Refractory patients will be switched to alternate TPO-RA agonist. Other reasons for switching that are not related to efficacy might include adverse events, active colitis, patient preference.

Official Title
-----------------
Randomized, Two-arm Single-center Phase II Clinical Trial Comparing the Efficacy and Safety of Romiplostim Versus Eltrombopag in the Treatment of Thrombocytopenia in Patients With Wiskott-Aldrich Syndrome

Conditions
-----------------
Wiskott-Aldrich Syndrome

Intervention / Treatment
-----------------
* Drug: Romiplostim
* Drug: Eltrombopag


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Genetically verified Wiskott-Aldrich syndrome Thrombocytopenia (platelet count < 70 x 109/L) Age: under 18 years Subject/legal representative has signed written informed consent. Exclusion Criteria: Patients, who do not meet the inclusion criteria. Any prior history of arterial or venous thrombosis within the past year. Arm II (eltrombopag): abnormal hepatic function -elevated AST/ALT > 1.5 times upper limit of normal within 4 weeks prior to enrollment Active colitis

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I (Romiplostim)<br>Participants will receive romiplostim at an initial dose of 9 µg/kg subcutaneously per week for at least 1 month depending on their response to study drug. Patients failing to achieve a complete platelet response cross over to arm II. | Drug: Romiplostim<br>* Participants will receive romiplostim at an initial dose of 9 µg/kg subcutaneously per week for at least 1 month depending on their response to study drug. Patients failing to achieve a complete platelet response cross over to arm II.<br>* Other names: Nplate;|
| Experimental: II (Eltrombopag)<br>Participants will receive eltrombopag at a dose of 2-3mg/kg daily (ages 0 to 5 years) and 75 mg/daily (>6 years) for at least 1 month depending on their response to study drug. Patients failing to achieve a complete platelet response switch to arm I. | Drug: Eltrombopag<br>* Participants will receive eltrombopag at a dose of 2-3mg/kg daily (ages 0 to 5 years) and 75 mg/daily (>6 years) for at least 1 month depending on their response to study drug. Patients failing to achieve a complete platelet response switch to arm I.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with overall platelet response (complete response + partial response) for romiplostim and eltrombopag group | A complete response will be defined as a platelet count >100 x 109/L, partial - 30 x 109/L higher than the patient's pretreatment baseline count to 100 x 109/L. | 1 month (30 day +/- 7 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with bleeding events and severity of bleeding in romiplostim and eltrombopag group | The incidence and severity of bleeding events is evaluated with a modified World Health Organization (WHO) Bleeding Scale. (G1=Petechiae, epistaxis <30 min, G2=Mild blood loss, hematomas, epistaxis >30 min, melanotic stool G3=Gross blood loss, requiring blood transfusions, G4=Fatal bleeding). | until discontinuation, from at least one month to one year | 
| Number of participants with drug related adverse events in each treatment group | Adverse events are graded according to Common Terminology Criteria for Adverse Events (CTCAE). | until discontinuation, from at least one month to one year | 
| Percentage of patients with overall platelet response (complete response + partial response) after switching from one TPO-RA to another one. |  | until discontinuation, from at least one month to one year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
eltrombopag, romiplostim, thrombocytopenia, platelets