Efficacy of Romiplostim in Treatment of SAA in Adults Previously Untreated With or Refractory to Immunosuppressive Therapy

Study Overview
=================
Brief Summary
-----------------
Romiplostim has been used in clinical trials for the treatment of severe and very severe aplastic anemia (SAA/vSAA) in Asian participants who are either previously untreated with immunosuppressive therapy (IST) or refractory to IST. This study will evaluate the efficacy of romiplostim in the treatment of participants with SAA/vSAA. The primary objectives of this study are to: Arm 1: Evaluate the efficacy of romiplostim and IST in adult SAA/vSAA participants who are previously untreated with IST (1L) Arm 2: Evaluate the efficacy of romiplostim treatment in adult SAA/vSAA participants who are refractory to IST (2L+)

Official Title
-----------------
Two Arm Bridging Study to Evaluate the Efficacy of Romiplostim in the Treatment of Adult Severe Aplastic Anemia Participants Who Are Either Previously Untreated With IST or Refractory to IST

Conditions
-----------------
Severe Aplastic Anemia (SAA)

Intervention / Treatment
-----------------
* Drug: Romiplostim
* Drug: Antithymocyte Globulin
* Drug: Cyclosporine A


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years at time of enrollment Diagnosis of SAA/vSAA confirmed by blood, bone marrow, and cytogenetic studies An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1 at screening Arm 1 only: participant requires initial treatment for SAA/vSAA, no matched related donor is available for allogenic hematopoietic cell transplantation (HCT) and will begin IST with antithymocyte globulin and CsA Arm 2 only: refractory to at least one course of immunosuppressive therapy including horse or rabbit ATG; or ineligible for ATG treatment and refractory to CsA Exclusion Criteria: Diagnosed as having congenital aplastic anemia (AA) (Fanconi anemia, congenital dyskeratosis, etc) History of other malignancy within the past 5 years, with exceptions. Aplastic anemia with hemolytic paroxysmal nocturnal hemoglobinuria (PNH) (hemolytic predominant is defined as lactate dehydrogenase (LDH) > 1.5 x the upper limit of site normal Arm 1 only: Previously treated with ATG, CsA, or Alemtuzumab Previously treated with PEGylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), recombinant human thrombopoietin protein (TPO), romiplostim and other TPO-receptor agonist (eltrombopag, etc) Patients who are eligible for allogenic HCT and have an available matched related donor

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Previously Untreated IST<br>Participants with SAA/vSAA that are previously untreated with IST. | Drug: Romiplostim<br>* Administered as a subcutaneous injection.<br>* Other names: Nplate®;Drug: Antithymocyte Globulin<br>* Horse or rabbit antithymocyte globulin administered as an intravenous infusion.<br>Drug: Cyclosporine A<br>* Administered orally.<br>|
| Experimental: Arm 2: Refractory IST<br>Participants with SAA/vSAA that are refractory to IST. | Drug: Romiplostim<br>* Administered as a subcutaneous injection.<br>* Other names: Nplate®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arms 1 and 2: proportion of participants achieving any hematologic response at week 14 | Proportion of participants achieving any hematologic response at week 14 based on response criteria: Platelet response Erythroid response Red blood cell count Hemoglobin concentration Neutrophil response | Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arm 1: number of participants who achieve a complete response (CR) or partial response (PR) at week 14 |  | Week 14 | 
| Arms 1 and 2: number of participants who have a decrease in frequency of platelet and/or red blood cell (RBC) transfusions, or become platelet and/or RBC transfusion independent at week 14 |  | Week 14 | 
| Arms 1 and 2: number of participants with serious adverse events |  | 24 Weeks | 
| Arms 1 and 2: number of participants with clinically significant changes in laboratory values |  | 24 Weeks | 
| Arms 1 and 2: change from baseline in Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) bleeding scale at week 14 | The Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto is as follows: 0: No bleeding Petecjoae or mucosal or retinal bleeding that did not require red-cell transfusion Melena, hematemesis, hematuria, or hemoptysis Any bleeding that required red-cell transfusion Retinal bleeding accompanied by visual impairment Nonfatal cerebral bleeding Fatal cerebral bleeding Fatal noncerebral bleeding | Baseline and Week 14 | 
| Arms 1 and 2: serum romiplostim trough concentrations |  | Prior to romiplostim administration on Weeks 1, 2, 4, 5, 9, 13, and 24 | 
| Arms 1 and 2: maximum serum concentration (Cmax) of romiplostim |  | Weeks 1, 2, 4, 5, 9, 13, and 24 | 
| Arms 1 and 2: area under the curve (AUC) of romiplostim |  | Weeks 1, 2, 4, 5, 9, 13, and 24 | 
| Arms 1 and 2: time to reach maximum concentration (tmax) of romiplostim |  | Weeks 1, 2, 4, 5, 9, 13, and 24 | 
| Arms 1 and 2: half-life (t1/2) of romiplostim |  | Weeks 1, 2, 4, 5, 9, 13, and 24 | 
| Arms 1 and 2: number of participant with anti-romiplostim antibodies |  | Prior to romiplostim administration on Weeks 1 and 13 | 
| Arms 1 and 2: number of participants with antibodies to thrombopoietin |  | Prior to romiplostim administration on Weeks 1 and 13 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SAA, Severe Aplastic Anemia, Very Severe Aplastic Anemia, vSAA, Romiplostim