16-Week Repeat Oral Dose Study of AKB-6548 for Anemia in Participants With End Stage Renal Disease (ESRD) Requiring Chronic Hemodialysis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the hemoglobin response (efficacy), safety, and tolerability of orally administered AKB-6548 in participants with end stage renal disease undergoing chronic hemodialysis.

Official Title
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Phase 2 Open-Label Study to Assess the Efficacy, Safety, and Tolerability of AKB-6548 in Subjects With Anemia Secondary to End Stage Renal Disease (ESRD), Undergoing Chronic Hemodialysis.

Conditions
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Anemia, End Stage Renal Disease

Intervention / Treatment
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* Drug: AKB-6548
* Drug: AKB-6548
* Drug: AKB-6548


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 18 to 79 years inclusive Chronic Kidney Disease (CKD) Stage 5 on chronic hemodialysis for at least 3 months Anemia secondary to CKD treated with erythropoiesis stimulating agent and intravenous iron Key Exclusion Criteria: Body mass index >44.0 kilograms per meter squared (kg/m^2) Transfusion within 8 weeks prior to Screening Alanine transaminase or total bilirubin >1.25x ULN Uncontrolled hypertension Class III or IV congestive heart failure Myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack within 6 months prior to Screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AKB-6548, starting dose 1<br> | Drug: AKB-6548<br>* Starting dose 1. Oral dose administered once daily for 16 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.<br>|
| Experimental: AKB-6548, starting dose 2<br> | Drug: AKB-6548<br>* Starting dose 2. Oral dose administered once daily for 16 weeks. Dose adjustment based on hemoglobin level as defined in the protocol.<br>|
| Experimental: AKB-6548, starting dose 3<br> | Drug: AKB-6548<br>* Starting dose 3. Oral dose administered three times weekly for 16 weeks. Dose adjustment based on hemoglobin levels as defined in the protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Pre-dose Average in Hemoglobin (Hgb) Level to The Mid-study Average | Change from pre-dose average was calculated by the mid-study average minus the pre-dose average. The pre-dose average was defined as the average of the 3 Hgb values that were obtained before dosing at the first screening visit, the second screening visit, and the Baseline visit; the mid-study average was defined as the average of the 2 Hgb values that were obtained at the Week 7 and Week 8 visits. | Pre-dose (Screening, Second Screening, and Baseline), Week 7, and Week 8 | 
| Change From Pre-dose Average in Hgb Level to The End-of-study Average | Change from pre-dose average was calculated by the end-of-study average minus the pre-dose average. The pre-dose average was defined as the average of the 3 Hgb values that were obtained before dosing at the first screening visit, the second screening visit, and the Baseline visit; the end-of-study average was defined as the average of the 2 Hgb values that were obtained at the Week 15 and Week 16 visits. | Pre-dose, Week 15, and Week 16 | 
| Change From Mid-study Average in Hgb Level to The End-of-study Average | Change from mid-study average was calculated by the end-of-study average minus the mid-study average. The mid-study average was defined as the average of the 2 Hgb values that were obtained at the Week 7 and Week 8 visits; the end-of-study average was defined as the average of the 2 Hgb values that were obtained at the Week 15 and Week 16 visits. | Week 7, Week 8, Week 15, and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hgb | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline Hgb was defined as the average of the three samples obtained prior to dosing. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Hematocrit | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline Hematocrit was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Red Blood Cell (RBC) Count | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline RBC Count was defined as the average of the three samples obtained prior to dosing. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Absolute Reticulocyte Count | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline absolute reticulocyte count was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Percent Reticulocyte Count | Change from Baseline was calculated as (visit value minus the Baseline value)/ Baseline value x 100. Baseline percent reticulocyte count was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Reticulocyte Hgb Content | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline reticulocyte Hgb content was defined as the average of the three samples obtained prior to dosing. | Baseline, Week 2, Week 4, Week 8, and Week 16 | 
| Change From Baseline in Ferritin | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline ferritin was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Hepcidin | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline hepcidin was defined as the last observation before the first dose of study medication. | Baseline, Week 8, and Week 16 | 
| Change From Baseline in Total Iron-Binding Capacity (TIBC) | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline TIBC was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Transferrin Saturation (TSAT) | Change from Baseline was calculated as (visit value minus the Baseline value)/ Baseline value x 100. Baseline TSAT was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Iron | Change from Baseline was calculated as the visit value minus the Baseline value. Baseline iron was defined as the last observation before the first dose of study medication. | Baseline, Week 4, Week 8, Week 12, and Week 16 | 
| Number of Participants Who Received Erythropoiesis-stimulating Agent (ESA) Rescue Therapy | ESA rescue therapy was administered in participants with Hgb ≤12.5 g/dL, and was stopped when Hgb reached ≥13.0 g/dL. | Up to Week 16 | 
| Number of Participants Who Received Blood Transfusion Rescue Therapy | Blood transfusion rescue therapy was administered in participants with Hgb ≤12.5 g/dL, and was stopped when Hgb reached ≥13.0 g/dL. | Up to Week 16 | 
| Mean Plasma Concentrations of Vadadustat | Blood samples for determination of plasma levels of Vadadustat were drawn just before and 10 minutes after completion of the dialysis session. | Pre-dialysis and post-dialysis on Week 2 and Week 16 | 
| Mean Plasma Concentrations of Vadadustat-O-Glucuronide Metabolite | Blood samples for determination of plasma levels of Vadadustat were drawn just before and 10 minutes after completion of the dialysis session. | Pre-dialysis and post-dialysis on Week 2 and Week 16 | 
| Mean Plasma Concentrations of Vadadustat-Acyl-Glucuronide Metabolite | Blood samples for determination of plasma levels of Vadadustat were drawn just before and 10 minutes after completion of the dialysis session. | Pre-dialysis and post-dialysis on Week 2 and Week 16 | 
| Number of Participants Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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. A TEAE 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. A SAE included AEs that met one or more of the following criteria/outcomes: death, lifethreatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, and congenital anomaly/birth defect. | Up to Week 20 | 
| Number of Participants With Clinically Significant Changes From Baseline in Vital Signs | Parameters assessed for vital signs included sitting blood pressure, pulse, respiratory rate, and body temperature. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to Week 20 | 
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values | Parameters assessed for laboratory values included hematology, serum chemistry, urinalysis, iron indices, C-reactive protein, lipid profile, biomarkers, and pregnancy tests. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to Week 20 | 
| Number of Participants With Clinically Significant Abnormal 12-Lead Electrocardiogram (ECG) Findings | A standard 12-lead ECG was performed following dosing in a supine position for approximately 5 minutes. ECGs were taken prior to vital sign assessments, circulatory access cannulation, and blood draws when possible. Clinical significance was determined by the investigator. | Up to Week 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic renal insufficiency, CKD, anemia, end stage renal disease, chronic kidney disease, dialysis, renal impairment, erythropoietin, kidney, oral anemia treatment, hemoglobin, hypoxia-inducible factor, HIF, hypoxia-inducible factor propyl-hydroxylase inhibitor, HIF-PHI, pharmacokinetics