Safety and Efficacy Study for AKB-6548 in Participants With Chronic Kidney Disease and Anemia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, pharmacodynamics and pharmacokinetics of repeat doses of orally administered AKB-6548 in pre-dialysis participants with anemia.

Official Title
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Phase 2a Open-Label Pilot Study to Assess the Pharmacodynamic Response, Pharmacokinetics, Safety, and Tolerability of 28-Day Repeat Oral Doses of AKB-6548 in Subjects With Anemia Secondary to Chronic Kidney Disease (CKD), Stages 3 and/or 4

Conditions
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Anemia, Kidney Disease

Intervention / Treatment
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* Drug: AKB-6548


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 18 to 79 years of age, inclusive Chronic Kidney Disease Stage 3 or Stage 4 Hemoglobin (Hgb) < 10.5 g/dl TSAT > 20% and CBC indicating normocytic red blood cell morphology Key Exclusion Criteria: BMI > 40 Red blood cell transfusion within 12 weeks. Androgen therapy within the previous 21 days prior to study dosing Therapy with any approved or experimental erythropoiesis stimulating agent (ESA) within the 10 weeks prior to the Screening visit Participants meeting the criteria of ESA resistance within the previous 4 months Individual doses of intravenous iron of 250 mg or larger within the past 21 days AST or ALT >1.8x ULN. Alkaline phosphatase >2x ULN. Total bilirubin >1.5x ULN. Uncontrolled hypertension New York Heart Association Class III or IV congestive heart failure Myocardial infarction, acute coronary syndrome, or stroke within 6 months prior to dosing

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AKB-6548<br> | Drug: AKB-6548<br>* Different dose levels<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Hemoglobin (Hgb) on Day 29 | Blood samples were collected to assess Hgb. Baseline Hgb was defined as the average of the 2 samples obtained prior to dosing (Pre-Baseline and Baseline). A positive change from baseline indicates that hemoglobin concentration increased. | Baseline; Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Hematocrit on Day 29 | Blood samples were collected to assess hematocrit. A positive change from baseline indicates hematocrit concentration increased. | Baseline; Day 29 | 
| Mean Change From Baseline in Total Red Blood Cell (RBC) Count on Day 29 | Blood samples were collected to assess RBC count. Baseline RBC count was defined as the average of the 2 samples obtained prior to dosing (Pre-Baseline and Baseline). A positive change from baseline indicates RBC count increased. | Baseline; Day 29 | 
| Mean Change From Baseline in Absolute Reticulocyte Count on Day 29 | Blood samples were collected to assess reticulocyte count. Baseline absolute reticulocyte count was defined as the average of the 3 reticulocyte counts obtained prior to dosing (Screening, Pre- Baseline, and Baseline). A positive change from baseline indicates absolute reticulocyte count increased. | Baseline; Day 29 | 
| Mean Change From Baseline in Reticulocyte Hemoglobin (Hgb) Content on Day 29 | Blood samples were collected to assess reticulocyte Hgb. Baseline Hgb was defined as the average of the 2 samples obtained prior to dosing (Pre-Baseline and Baseline). A positive change from baseline indicates reticulocyte Hgb content increased. | Baseline; Day 29 | 
| Number of Participants With Absolute Change From Baseline in Hemoglobin (Hgb) at Day 29 | Blood samples were collected to assess Hgb. Baseline Hgb was defined as the average of the 2 samples obtained prior to dosing (Pre-Baseline and Baseline). | Day 29 | 
| Number of Participants With the Percentage Change From Baseline in Hemoglobin (Hgb) at Day 29 | Blood samples were collected to assess Hgb. Baseline Hgb was defined as the average of the 2 samples obtained prior to dosing (Pre-Baseline and Baseline). | Day 29 | 
| Number of Participants With Percentage Change From Baseline in Hematocrit at Day 29 | Blood samples were collected to assess hematocrit. | Day 29 | 
| Number of Participants With Percentage Change From Baseline in Red Blood Cell (RBC) Count at Day 29 | Blood samples were collected to assess RBC count. Baseline RBC count was defined as the average of the 2 samples obtained prior to dosing (Pre-Baseline and Baseline). | Day 29 | 
| Number of Participants With Change From Baseline in Absolute Reticulocyte Count at Day 29 | Blood samples were collected to assess reticulocyte count. Baseline absolute reticulocyte count was defined as the average of the 3 reticulocyte counts obtained prior to dosing (Screening, Pre- Baseline, and Baseline). | Day 29 | 
| Change From Baseline in Ferritin on Day 29 | Blood samples were collected to assess ferritin. A positive change from baseline indicates ferritin content increased. | Baseline; Day 29 | 
| Change From Baseline in Iron on Day 29 | Blood samples were collected to assess iron. A positive change from baseline indicates iron content increased. | Baseline; Day 29 | 
| Change From Baseline in Total Iron Binding Capacity on Day 29 | Blood samples were collected to assess total iron binding capacity. A positive change from baseline indicates total iron binding capacity increased. | Baseline; Day 29 | 
| Change From Baseline in Transferrin Saturation on Day 29 | Blood samples were collected to assess transferrin saturation. The transferrin saturation is the ratio of the serum iron concentration and the total iron-binding capacity, expressed as a percentage. A positive change from baseline indicates transferrin saturation increased. | Baseline; Day 29 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An Adverse Event (AE) was defined as any untoward medical occurrence, signs, symptoms, disease, or laboratory or physiological observations occurring in a participant administered with drug, regardless of a causal relationship with that treatment or usage. This also included all suspected adverse medication reactions, reactions from medication overdose, abuse, withdrawal, sensitivity, toxicity, unrelated illnesses, including worsening a pre-existing condition, injury, or accidents. Serious Adverse Events (SAEs) was defined as any life-threatening condition; hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; or death. | Up to 2 weeks post 28 days of treatment | 
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values | Parameters assessed for laboratory values included hematology, chemistry, urinalysis, and coagulation. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to 2 weeks post 28 days of treatment | 
| Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Values | Parameters assessed for vital signs included sitting (at rest for a minimum of 5 minutes) heart rate, respiratory rate, body temperature, and blood pressure. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to 2 weeks post 28 days of treatment | 
| Number of Participants With Clinically Abnormal 12-Lead Electrocardiogram (ECG) Findings | A standard 12-lead ECG was performed following dosing in a supine position for approximately 10 minutes. ECGs were taken prior to blood draws when possible. The investigator was responsible for reviewing laboratory results for clinical significance. | Up to 2 weeks post 28 days of treatment | 
| Mean Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval | A standard 12-lead ECG was performed following dosing in a supine position for approximately 10 minutes. ECGs were taken prior to blood draws when possible. The parameters evaluated from the participant ECG trace included PR interval, QT interval, QRS interval, and QTc (corrected). | Up to 2 weeks post 28 days of treatment | 
| Mean Trough Concentrations of Vadadustat at Day 8, 15, 22 and 29 | Serum samples were collected from the participants at the defined time points. Trough concentration was defined as the concentration of drug in the blood immediately before the next dose is administered. Trough concentration was calculated using the validated liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method | Pre-dose at Day 8, 15, 22 and 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anemia, chronic kidney disease, CKD, chronic renal insufficiency, renal impairment, erythropoietin, safety, efficacy, tolerability, pharmacokinetics