Study to Assess the Safety and Pharmacokinetics of AKB-6548 in Participants With Chronic Kidney Disease (CKD), Stages 3 and 4

Study Overview
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Brief Summary
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This study was conducted to assess the pharmacokinetic (PK) profile, safety, and tolerability in participants with Stage 3 and 4 Chronic Kidney Disease (CKD) following a single oral dose of Vadadustat.

Official Title
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A Phase 2A Single Dose, Open Label Study to Assess the Safety and Pharmacokinetics of AKB-6548 in Subjects With Chronic Kidney Disease (CKD), Stages 3 and 4

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Drug: Vadadustat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 79 years of age, inclusive Chronic Kidney Disease Stage 3 (Estimated Glomerular Filtration Rate [eGFR] 30 to 59 milliliters [mL]/minute) or Stage 4 participants (eGFR of <30 mL/minute that were not yet on dialysis). eGFR was calculated using the Modification of Diet in Renal Disease (MDRD). Hemoglobin (Hb) <13.5 grams per deciliter (g/dL) except for Polycystic Kidney Disease (PKD) participants, in which Hb was to be ≤14 g/dL Transferrin saturation (TSAT) >12% and complete blood count (CBC) indicating normocytic red blood cell morphology, unless the medical monitor and investigator agreed that the participant was appropriate for this study Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.8 x upper limit of normal (ULN) Alkaline phosphatase ≤2 x ULN Bilirubin ≤1.5 x ULN Female participants were not pregnant or breastfeeding. Women of childbearing potential agreed to use an acceptable method of contraception. Non-vasectomized male participants agreed to use an acceptable method of contraception Understood the procedures and requirements of the study and provided written informed consent and authorization for protected health information disclosure Exclusion Criteria: Any medical or psychological condition that in the opinion of the Investigator would have interfered with the participant's ability to provide informed consent or comply with study instructions Any clinically significant or uncontrolled medical condition that in the opinion of the Investigator would have placed the participant at undo risk or would have compromised the interpretability of the findings in this study A body mass index (BMI) of greater than 40 Seropositive for human immunodeficiency virus (HIV) or Hepatitis B surface antigen Seropositive for Hepatitis C virus (HCV) antibodies unless ALT, AST, bilirubin tests were within normal limits History of chronic liver disease Uncontrolled hypertension (diastolic blood pressure [BP] > 110 millimeters of mercury [mm Hg] or systolic BP >190 mm Hg at screening) New York Heart Association Class III or IV congestive heart failure Myocardial infarction, acute coronary syndrome, or stroke within 6 months of dosing History of myelodysplastic syndrome Participants known to have diabetic gastroparesis that was either symptomatic on therapy or was refractory to therapy Any history of malignancy in the previous 5 years except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps Evidence of active infection unless the medical monitor and investigator agreed that the participant was appropriate for this study History of rheumatoid arthritis or systemic lupus erythematosus (SLE) (History of osteoarthritis or gout did not exclude participants from eligibility in the study.) Age-related macular degeneration (AMD), diabetic macular edema or active diabetic proliferative retinopathy that was likely to require treatment during the trial History of deep vein thrombosis (DVT) that required active treatment. Superficial thrombosis was not excluded. History of ongoing hemolysis or diagnosis of hemolytic syndrome Known history of bone marrow fibrosis History of hemosiderosis or hemochromatosis Androgen therapy within 21 days from the last injection Red blood cell transfusion within 12 weeks Therapy with an erythropoiesis stimulating agent (ESA) such as human recombinant erythropoietin within the past 21 days Intravenous iron supplementation within the past 21 days Currently taking acetaminophen > 2.6 grams/day History of prior organ transplantation, or stem cell or bone marrow transplantation Alcohol consumption greater than 14 or more drinks per week within the past year (1 drink = 12 ounce [oz] beer, 5 oz wine, or 1.5 oz hard liquor.) Use of an investigational medication or participation in an investigational study within 30 days, or 5 half-lives of the investigational product, whichever was longer, preceding Day 1 Positive urine toxicology screen for a substance of abuse that had not been prescribed for the participant

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: CKD, Stage 3<br>Participants with Stage 3 Chronic Kidney Disease (CKD) (Estimated Glomerular Filtration Rate [eGFR] 30 - 59 milliliters [mL]/minute) received a single 500 milligram (mg) oral dose of Vadadustat after fasting for at least 4 hours. | Drug: Vadadustat<br>* oral capsules<br>* Other names: AKB-6548;|
| Experimental: CKD, Stage 4<br>Participants with Stage 4 CKD (eGFR <30 mL/minute and not yet on dialysis) received a single 500 mg oral dose of Vadadustat after fasting for at least 4 hours. | Drug: Vadadustat<br>* oral capsules<br>* Other names: AKB-6548;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An Adverse Event (AE) was defined as any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a human being participating in a clinical study following study medication administration, regardless of causal relationship. This also included any clinically significant worsening or re-occurrence of a pre-existing condition, or AE occurring from an overdose of a study drug whether accidental or intentional or AE occurring from abuse of study drug or that has been associated with the discontinuation of the use of study drug. | Up to Day 8 | 
| 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 Day 8 | 
| 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. Number of participants with a clinically significant change from baseline in at least one of the assessed vital signs parameters is reported. | Up to Day 8 | 
| 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 Day 2 | 
| 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). The baseline was defined as Day 1 pre-dose measurement. If missing, the last measurement prior to dosing was used. | Baseline; Day 2 | 
| Change From Baseline in Heart Rate | The heart rate evaluation was performed after the participant had been resting comfortably in a supine position for approximately 10 minutes. | Baseline; Day 2 | 
| Number of Participants With Clinically Significant Changes From Baseline in Physical Examination Findings | A baseline physical examination was performed at screening. Otherwise, abbreviated physical examinations were conducted and were to include heart, lung, and abdomen. The investigator was responsible for reviewing laboratory results for clinically significant changes. | Up to Day 8 | 
| Geometric Mean Maximum Observed Plasma Concentration (Cmax) of AKB-6548 | Plasma samples were collected from the participants at the defined time points. Cmax was defined as the maximum observed plasma concentration. Cmax was calculated using the standard non-compartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Median Time to Reach Cmax (Tmax) of AKB-6548 | Plasma samples were collected from the participants at the defined time points. Tmax was defined as the time to reach maximum plasma concentration. Tmax was calculated using the standard non-compartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Mean Terminal Elimination Rate Constant (λz) | Plasma samples were collected from the participants at the defined time points. λz was calculated using linear regression of the terminal linear portion of the log concentration vs. time curve. The parameter was calculated by linear least-squares regression analysis using three or more concentrations, excluding Cmax. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Median Terminal Elimination Half-life (T½) | Plasma samples were collected from the participants at the defined time points. T½ was defined as apparent terminal elimination half-life. T½ was calculated using the standard non-compartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Geometric Mean Area Under the Plasma Concentration-time Curve From 0 to Time T Over a Dosing Interval (AUC[0-T]) | Plasma samples were collected from the participants at the defined time points. AUC[0-T) was defined as the area under the plasma concentration-time curve, from time=0 to the last measurable concentration (Ct) up to 24 hours, calculated by the linear trapezoidal method. AUC[0-T) was calculated using the standard noncompartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Geometric Mean Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) | Plasma samples were collected from the participants at the defined time points. AUC[0-∞] was defined as the area under the plasma concentration-time curve from time=0 and extrapolated to infinity. AUC[0-∞] was calculated using the standard non-compartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Geometric Mean Apparent Oral Clearance (CL/F) | Plasma samples were collected from the participants at the defined time points. CL/F was defined as apparent oral clearance, calculated as Dose/AUC(0-inf). CL/F was calculated using the standard non-compartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 
| Geometric Mean Apparent Volume of Distribution During the Terminal Phase (Vd/F) | Plasma samples were collected from the participants at the defined time points. Vd/F was defined as the apparent volume of distribution during the terminal phase, calculated as Dose/[λz * AUC(0-inf)]. Vd/F was calculated using the standard non-compartmental method. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Erythropoietin (EPO) | The change from baseline was calculated by subtracting the baseline value from the individual post-dose visit values. | Baseline; 8, 12, and 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CKD, CKD, Stage 3, CKD, Stage 4, Vadadustat, pharmacokinetics