Dose-Finding Study of Vadadustat in Japanese Subjects With Anemia Secondary to Dialysis-Dependent Chronic Kidney Disease (DD-CKD)

Study Overview
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Brief Summary
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This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding study to assess the efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of orally administered vadadustat in Japanese participants with anemia secondary to Dialysis-dependent Chronic Kidney Disease (DD-CKD).

Official Title
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Phase 2, Randomized, Double-Blind, Placebo Controlled, Dose-Finding Study to Assess the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Vadadustat in Japanese Subjects With Anemia Secondary to Dialysis-Dependent Chronic Kidney Disease (DD-CKD)

Conditions
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Anemia, Dialysis Dependent Chronic Kidney Disease

Intervention / Treatment
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* Drug: Vadadustat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female Japanese participants ≥20 years of age Receiving chronic maintenance hemodialysis for end-stage kidney disease Hemoglobin (Hb) <10.0 grams per deciliter (g/dL) Exclusion Criteria: Anemia due to a cause other than chronic kidney disease (CKD) or presence of active bleeding or recent blood loss Sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia Red blood cell transfusion within 4 weeks prior to or during screening Anticipated to recover adequate kidney function to no longer require hemodialysis during study participation

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vadadustat, Dose 1<br>Daily oral dose | Drug: Vadadustat<br>* Daily oral dose<br>* Other names: AKB-6548;|
| Experimental: Vadadustat, Dose 2<br>Daily oral dose | Drug: Vadadustat<br>* Daily oral dose<br>* Other names: AKB-6548;|
| Experimental: Vadadustat, Dose 3<br>Daily oral dose | Drug: Vadadustat<br>* Daily oral dose<br>* Other names: AKB-6548;|
| Placebo Comparator: Placebo<br>Daily oral dose | Drug: Placebo<br>* Daily oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period | The pre-treatment average value for Hb was defined as the average of 3 values obtained prior to treatment, i.e., the qualifying screening value and the Baseline value. Change from Pre-treatment was calculated as the Week 6 value minus the Pre-treatment value. | Pre-treatment; Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | Time for this analysis was measured from Day 1 (Baseline) through the point in time during either the Primary Efficacy Period or the Dose Adjustment and Maintenance Period when a participant's Hb level achieved the target range of 10.0 to 12.0 g/dL. | from Baseline up to Week 16 | 
| Mean Hb Levels at the End of the Primary Efficacy Period | Data are reported as mean of the actual Week 6 values. | up to Week 6 | 
| Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | Data are reported as mean of the actual Week 16 values. | up to Week 16 | 
| Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period |  | up to Week 16 | 
| Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | A pre-treatment average value for Hb was defined as the average of 3 values obtained prior to dosing, i.e., the 2 qualifying screening values and the Baseline value. Change from Pre-treatment was calculated as the Week 16 value minus the Pre-treatment value. | Pre-treatment; Week 16 | 
| Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 6 | 
| Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 16 | 
| Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 6 | 
| Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 16 | 
| Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 6 | 
| Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 16 | 
| Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 6 | 
| Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 16 | 
| Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 6 | 
| Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 16 | 
| Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period | Participants who initiated rescue therapy (including RBC transfusion) were required to stop study drug treatment and were discontinued from the study. | Baseline; Week 6 | 
| Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | Participants who initiated rescue therapy (including RBC transfusion) were required to stop study drug treatment and were discontinued from the study. | Baseline; Week 16 | 
| Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period | ESA rescue is defined as participants with ESA administration and 1) the participant experienced a clinically significant worsening of their anemia or symptoms of anemia, 2) the participant's Hb level is <9.0 g/dL, and 3) reason for early study withdrawal of worsening of anemia requiring ESA rescue or blood transfusion. Participants who initiated rescue therapy (including ESAs) were required to stop study drug treatment and were discontinued from the study. | Baseline; Week 6 | 
| Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | ESA rescue is defined as participants with ESA administration and 1) the participant experienced a clinically significant worsening of their anemia or symptoms of anemia, 2) the participant's Hb level is <9.0 g/dL, and 3) reason for early study withdrawal of worsening of anemia requiring ESA rescue or blood transfusion. Participants who initiated rescue therapy (including ESAs) were required to stop study drug treatment and were discontinued from the study. | Baseline; Week 16 | 
| Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | Increases in dose were not allowed during the 6-week Primary Efficacy Period. | up to Week 16 | 
| Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Blood samples were collected for analysis. | Week 4, pre-dose | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | An adverse event (AE) was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. An AE that met one or more of the following criteria or outcomes was classified as serious: death; life-threatening; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; was considered a medically important event not meeting the above criteria, but which could jeopardize a participant, or could require medical or surgical intervention to prevent one of the criteria listed in this definition. | up to Week 6 | 
| Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | An AE was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. An AE that met one or more of the following criteria or outcomes was classified as serious: death; life-threatening; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; was considered a medically important event not meeting the above criteria, but which could jeopardize a participant, or could require medical or surgical intervention to prevent one of the criteria listed in this definition. | up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anemia, kidney, dialysis dependent chronic kidney disease, CKD, DD, renal, vadadustat, AKB-6548, hypoxia-inducible factor, Akebia (AKB), hypoxia-inducible factor (HIF), HIF, prolyl-hydroxylase inhibitor (PHI), PHI, Japan, Japanese