Efficacy and Safety of Roxadustat for Treatment of Anemia in Participants With Lower Risk Myelodysplastic Syndrome With Low Red Blood Cell Transfusion Burden

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether FG-4592 is safe and effective in the treatment of anemia in participants with lower risk MDS and low red blood cell transfusion burden.

Detailed Description
-----------------
This study includes an Open-Label Lead in, a Double-Blind component, and an Open-Label High Erythropoietin component. There is a screening period of up to 42 days followed by a treatment period of 52 weeks and a 4-week end of treatment assessment.

Official Title
-----------------
A Phase 3 Randomized Double-Blind Placebo-Controlled Study Investigating the Efficacy and Safety of Roxadustat (FG-4592) for Treatment of Anemia in Patients With Lower Risk Myelodysplastic Syndrome (MDS) With Low Red Blood Cell (RBC) Transfusion Burden (LTB)

Conditions
-----------------
Primary MDS (Very Low, Low or Intermediate IPSS-R With <5% Blasts)

Intervention / Treatment
-----------------
* Drug: Roxadustat
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Diagnosis of primary MDS classified by the International Prognostic Scoring System - Revised (IPSS-R) as very low, low or intermediate risk with <5% bone marrow blasts. There is no minimum time from diagnosis to registration/randomization except to allow for proper IPSS-R classification to be made (within 16 weeks prior to randomization), and to show transfusion dependence for participants in both portions of the study. RBC transfusion of either 2-4 pRBC units during the 8 weeks prior to registration/randomization or 1 pRBC in two consecutive periods of 8 weeks within the 16 weeks prior to registration/randomization. Open-Label Lead-in participants only, the requirement to demonstrate transfusion dependence can also be met by a Principal Investigator starting this particular participant on pRBC transfusion during the screening period. No restriction on prior use of recombinant erythropoietins or analogues (erythropoiesis-stimulating agents [ESAs]), except no ESA use within 8 weeks prior to Day 1 registration/randomization. Hemoglobin (Hb) ≤10.0 grams/deciliter (g/dL) during screening Eastern Cooperative Oncology Group (ECOG) of 0-2 at screening Key Exclusion Criteria: Diagnosis of secondary MDS associated with prior chemotherapy, extensive radiation therapy (>25% of bone marrow reserve), and or/other significant chemical or radiation exposure Significant myelofibrosis (>2+ fibrosis) MDS associated with 5q(del) cytogenetic abnormality Screen serum erythropoietin level > 400 milli-international units (mIU)/milliliter (mL) • Clinically significant anemia, as determined by the investigator, due to non-MDS etiologies such as iron deficiency, vitamin B12 or folate deficiency, autoimmune or hereditary hemolysis or anemia or hemorrhage or hereditary anemia such as sickle cell anemia or thalassemia.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Roxadustat<br>Open-label, lead-in: Participants will receive sequential escalating roxadustat doses (1.5 milligrams/kilograms [mg/kg], 2.0 mg/kg and 2.5 mg/kg), three times a week (TIW) based upon their actual weight at the randomization visit to identify the starting dose for double-blind period. Double-blind: Participants will receive roxadustat 2.5 mg/kg TIW based upon their body weight for a duration of 52 weeks. Open-label: Participants with high serum erythropoietin levels (>400 milli-international units [mIU]/milliliter [mL] mIU/mL) will receive roxadustat 2.5 mg/kg TIW based upon their body weight for a duration of 52 weeks. | Drug: Roxadustat<br>* Oral tablets<br>* Other names: AZD9941;|
| Placebo Comparator: Placebo<br>Double-blind: Participants will receive placebo matching to roxadustat for a duration of 52 weeks. | Drug: Placebo<br>* Oral tablets<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve Transfusion Independence (TI) ≥56 Consecutive Days in the First 28 Weeks of Treatment |  | 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants who Achieve TI ≥56 Consecutive Days Anytime During the Study |  | Weeks 28 and 52 | 
| Percentage of Participants who Achieve ≥50% Reduction From Baseline in Number of RBC Transfusion Over Any 8 Weeks |  | Weeks 28 and 52 | 
| Cumulative Number of Participant-Exposure-Week of TI |  | Weeks 28 and 52 | 
| Number of Packs of Red Blood Cells (pRBC) Packs Transfused Compared to Baseline |  | Weeks 28 and 52 | 
| Percentage of Participants who Achieved TI for > 20 Weeks (140 Days) |  | Weeks 28 and 52 | 
| Mean Change From Baseline in Physical Function as Measured by Patient Reported Outcomes Measurement Information System (PROMIS) |  | Baseline, Weeks 9, 17, 28, 52 and 56 | 
| Mean Change From Baseline in PROMIS Fatigue Score |  | Baseline, Weeks 9, 17, 28, 52 and 56 | 
| Mean Change From Baseline in EuroQol Quality of Life Five Dimensional Five Level Health Questionnaire (EQ-5D-5L) Assessment Score |  | Baseline, Weeks 9, 17, 28, 52 and 56 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myelodysplastic Syndromes, Anemia, Hemoglobin (Hb), Low Risk Myelodysplastic Syndrome, Low Risk MDS