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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04707573

Enrollment

Registered

2021-01-13

Start date

2010-07-08

Completion date

2010-09-24

Last updated

2022-06-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Kidney Disease

Keywords

CKD, CKD, Stage 3, CKD, Stage 4, Vadadustat, pharmacokinetics

Brief summary

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.

Interventions

DRUGVadadustat

oral capsules

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 79 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Geometric Mean Apparent Volume of Distribution During the Terminal Phase (Vd/F)	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Geometric Mean Maximum Observed Plasma Concentration (Cmax) of AKB-6548	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Median Time to Reach Cmax (Tmax) of AKB-6548	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Mean Terminal Elimination Rate Constant (λz)	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Median Terminal Elimination Half-life (T½)	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Geometric Mean Area Under the Plasma Concentration-time Curve From 0 to Time T Over a Dosing Interval (AUC[0-T])	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Geometric Mean Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-∞])	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Geometric Mean Apparent Oral Clearance (CL/F)	Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2)	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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	Up to Day 8	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.
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values	Up to Day 8	Parameters assessed for laboratory values included hematology, chemistry, urinalysis, and coagulation. The investigator was responsible for reviewing laboratory results for clinically significant changes.
Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Values	Up to Day 8	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.
Number of Participants With Clinically Abnormal 12-Lead Electrocardiogram (ECG) Findings	Up to Day 2	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.
Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline; Day 2	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.
Change From Baseline in Heart Rate	Baseline; Day 2	The heart rate evaluation was performed after the participant had been resting comfortably in a supine position for approximately 10 minutes.
Number of Participants With Clinically Significant Changes From Baseline in Physical Examination Findings	Up to Day 8	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.

Secondary

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

Other

Measure	Time frame
Exploratory: Change From Baseline in Vascular Endothelial Growth Factor (VEGF) at 24 Hours	Baseline; 24 hours post-dose
Exploratory: Change From Baseline in Transferrin at 24 Hours	Baseline; 24 hours post-dose
Exploratory: Change From Baseline in Hepcidin at 24 Hours	Baseline; 24 hours post-dose
Exploratory: Change From Baseline in Adiponectin at 24 Hours	Baseline; 24 hours post -dose
Exploratory: Change From Baseline in Ferritin at 24 Hours	Baseline; 24 hours post-dose
Exploratory: Change From Baseline in Cystatin-C at 24 Hours	Baseline; 24 hours post -dose

Countries

United States

Participant flow

Pre-assignment details

A total of 22 participants were enrolled in this study. The participants were placed in one of two cohorts, depending on disease state: Chronic Kidney Disease (CKD) Stage 3 (Cohort 1) or CKD Stage 4 (Cohort 2).

Participants by arm

Arm	Count
Cohort 1: CKD Stage 3 Vadadustat Participants with CKD Stage 3 with Estimated Glomerular Filtration Rate (eGFR) 30 - 59 mL/minute received a single dose of Vadadustat 500 milligrams (mg) (one 200 mg capsule and one 300 mg capsule) orally in fasted condition.	10
Cohort 2: CKD Stage 4 Vadadustat Participants with CKD Stage 4 with eGFR \<30 mL/minute and not yet on dialysis received a single dose of Vadadustat 500 milligrams (mg) (one 200 mg capsule and one 300 mg capsule) orally in fasted condition.	12
Total	22

Baseline characteristics

Characteristic	Cohort 1: CKD Stage 3 Vadadustat	Cohort 2: CKD Stage 4 Vadadustat	Total
Age, Continuous	63.0 years STANDARD_DEVIATION 12.9	64.4 years STANDARD_DEVIATION 10	63.8 years STANDARD_DEVIATION 11.1
Estimated Glomerular Filtration Rate	45.22 mL/min/1.73m^2 STANDARD_DEVIATION 8.54	24.39 mL/min/1.73m^2 STANDARD_DEVIATION 3.31	33.86 mL/min/1.73m^2 STANDARD_DEVIATION 12.23
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants	12 Participants	22 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	9 Participants	11 Participants	20 Participants
Sex: Female, Male Female	5 Participants	8 Participants	13 Participants
Sex: Female, Male Male	5 Participants	4 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 12
other Total, other adverse events	6 / 10	2 / 12
serious Total, serious adverse events	0 / 10	0 / 12

Outcome results

Primary

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.

Time frame: Baseline; Day 2

Population: ITT Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in Heart Rate	Change from Baseline at Day 2	5.2 Beats per minute	Standard Deviation 6.3
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in Heart Rate	Baseline	59.8 Beats per minute	Standard Deviation 9
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in Heart Rate	Baseline	64.3 Beats per minute	Standard Deviation 5.6
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in Heart Rate	Change from Baseline at Day 2	1.8 Beats per minute	Standard Deviation 3.7

Primary

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.

Time frame: Baseline; Day 2

Population: ITT Population

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline QTc interval	423.5 Milliseconds	Standard Deviation 22.8
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 PR interval	-12.4 Milliseconds	Standard Deviation 28.4
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 QT interval	-13.8 Milliseconds	Standard Deviation 21.8
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline QRS interval	98.8 Milliseconds	Standard Deviation 20.7
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 QTc interval	3.1 Milliseconds	Standard Deviation 10.2
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 QRS interval	-0.8 Milliseconds	Standard Deviation 3.2
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline PR interval	178.8 Milliseconds	Standard Deviation 44.2
Cohort 1: CKD Stage 3 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline QT interval	427.2 Milliseconds	Standard Deviation 22
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 QTc interval	2.0 Milliseconds	Standard Deviation 18.2
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline QT interval	426.5 Milliseconds	Standard Deviation 39.7
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 QT interval	-2.3 Milliseconds	Standard Deviation 16.7
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline QTc interval	439.5 Milliseconds	Standard Deviation 35.8
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline PR interval	182.5 Milliseconds	Standard Deviation 24.2
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 PR interval	-3.5 Milliseconds	Standard Deviation 5.5
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Baseline QRS interval	97.7 Milliseconds	Standard Deviation 26
Cohort 2: CKD Stage 4 Vadadustat	Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval	Change from Baseline at Day 2 QRS interval	0.0 Milliseconds	Standard Deviation 5.4

Primary

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.