A Phase 2 Study to Evaluate the Efficacy and Safety of AMG531 in Aplastic Anemia

Study Overview
=================
Brief Summary
-----------------
The present study will be conducted to evaluate the efficacy and safety of AMG531 and to determine the recommended initial dose of AMG531 on the basis of its efficacy and safety when it is administered subcutaneously (SC) to the Aplastic Anemia (AA) patients with immunosuppressive-therapy refractory thrombocytopenia and also to assess the pharmacokinetics of this product. Its efficacy and safety during the extension period beyond one year will also be evaluated.

Official Title
-----------------
A Phase 2, Randomized, Open-Label, Parallel, Comparative, Dose-Finding Study to Evaluate the Efficacy and Safety of AMG531 in Aplastic Anemia Subjects With Thrombocytopenia Refractory to Immunosuppressive Therapy

Conditions
-----------------
Aplastic Anemia

Intervention / Treatment
-----------------
* Drug: AMG531


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient who is diagnosed as AA and refractory to immunosuppressive therapy Platelet ≤ 30,000/μL Exclusion Criteria: Concurrent active infection not adequately responding to appropriate therapy HIV positivity Bone marrow reticulin grade of > 1 Clinically significant cardiac disease Arterial or venous thrombosis within the last 1 year before enrollment Other cause of thrombocytopenia AA with hemolytic predominant paroxysmal nocturnal hemoglobinuria (PNH) Uncontrolled diabetes Receiving any agent used to treat AA, including antithymocyte globulin (ATG) or ATG + cyclosporine within 6 months before starting study treatment and/or cyclosporine or anabolic hormone within 6 weeks before starting the study treatment History of PEG-rHuMGDF, recombinant human thrombopoietin, AMG531, and other thrombopoietin (TPO)-receptor agonist Who plans to conduct hematopoietic stem cell transplantation within 1 year

Ages Eligible for Study
-----------------
Minimum Age: 19 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG531 (Dose 1)<br> | Drug: AMG531<br>* Subcutaneous, weekly injection<br>|
| Experimental: AMG531 (Dose 2)<br> | Drug: AMG531<br>* Subcutaneous, weekly injection<br>|
| Experimental: AMG531 (Dose 3)<br> | Drug: AMG531<br>* Subcutaneous, weekly injection<br>|
| Experimental: AMG531 (Dose 4)<br> | Drug: AMG531<br>* Subcutaneous, weekly injection<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Achieving a Platelet Response at Week 9 | The proportion of subjects achieving a platelet response at Week 9, and two-sided 95% confidence interval will be calculated. Platelet response is defined as 1) achieving absolute platelet increase of ≥ 20x10^9/L above baseline or 2) increase to ≥ 10x10^9/L and by at least 100% from baseline. | At week 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Achieving a Platelet Response | The proportion of subjects with a platelet response in any time during the initial dose evaluation period, Week 1 through Week 12, Week 1 through Week 16, Week 1 through Week 24, Week 1 through Week 52, Week 1 through Week 104 and Week 1 through Week 156. | Initial dose evaluation period (Week 9), Week 12, Week 16, Week 24, Week 52, Week 104, and Week 156 | 
| Proportion of Subjects Achieving Platelet Transfusion Independency | The proportion of subjects achieving platelet transfusion independency in any time during the initial dose evaluation period , Week 1 through Week 12, Week 1 through Week 16, Week 1 through Week 24, Week 1 through Week 52, Week 1 through Week 104, and Week1 through Week 156 will be calculated in the same manner as the primary variables (The number of subjects discontinued or subjects who have missing data will not be calculated). Platelet transfusion independence is defined as achieving transfusion free period of at least 8 consecutive weeks (56 days). | Initial dose evaluation period (Week 9), Week 12, Week 16, Week 24, Week 52, Week 104, and Week 156 | 
| Proportion of Subjects Achieving Erythroid Response and/or Neutrophil Response | The proportion of subjects with erythroid response, neutrophil response and erythroid and/or neutrophil response in any time during the initial dose evaluation period, Week 1 through Week 12, Week 1 through Week 16, Week 1 through Week 24, Week 1 through Week 52, Week 1 through Week 104, and Week1 through Week 156 will be calculated in the same manner as the primary variables (The number of subjects discontinued or subjects who have missing data will not be calculated). | Initial dose evaluation period (Week 9), Week 12, Week 16, Week 24, Week 52, Week 104, and Week 156 | 
| Duration of Platelet Response and Time to Platelet Response | For subjects with a platelet response in any time, time to the initial platelet response and duration of platelet response will be summarized Time to the initial platelet response will be calculated as sampling date (response achieved) minus first dose date of study drug plus 1. Duration of platelet response will be calculated as the maximum of the duration of platelet response for each subject, each duration of response calculated as the date when response is disappeared minus the date when response is achieved. The censoring date is defined as the date of the last Platelet examination or EOS whichever archives first. | Initial dose evaluation period (Week 9), Week 12, Week 16, Week 24, Week 52, Week 104, and Week 156 | 
| Proportion of Subjects Achieving Tri-lineage Responses | Tri-lineage response is defined in those achieving platelet response, erythroid response, and neutrophil response all together. The proportion of subjects with tri-lineage response will be calculated in the same manner as the primary variables. Time to tri-lineage response will be summarized in the same manner as time to platelet response. Time to tri-lineage response is defined as duration of the time from Day 1 to the date of platelet response, erythroid response or neutrophil response whichever achieves last in Visit. | Initial dose evaluation period (Week 9), Week 12, Week 16, Week 24, Week 52, Week 104, and Week 157 | 
| Duration of Study Drug Discontinuation While Maintaining Stable Response | The longest duration of study drug discontinuation in subjects while maintaining a stable response is summarized | Initial dose evaluation period (Week 9), Week 12, Week 16, Week 24, Week 52, Week 104, and Week 156 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Thrombopoietin, Anemia, Aplastic, Thrombocytopenia