Study to Assess the Safety and Pharmacokinetics of AKB-6548 in Participants With Chronic Kidney Disease (CKD), Stages 3 and 4
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CKD, Stage 3 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
oral capsules
Other Names:
|
| Experimental: CKD, Stage 4 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
oral capsules
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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.
- 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.
- 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.
Secondary Outcome Measures
- 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 Outcome Measures
- Exploratory: Change From Baseline in Hepcidin at 24 Hours [Baseline; 24 hours post-dose]
- 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 Cystatin-C 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]
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Saint Paul | Minnesota | United States | 55114 |
| 2 | Research Site | Knoxville | Tennessee | United States | 37920 |
Sponsors and Collaborators
- Akebia Therapeutics
Investigators
- Study Director: Chief Medical Officer, Akebia Therapeutics Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- AKB-6548-CI-0003
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 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). |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | Participants with CKD Stage 3 with Estimated Glomerular Filtration Rate (eGFR) 30 - 59 milliliter (mL)/minute received a single dose of Vadadustat 500 milligrams (mg) (one 200 mg capsule and one 300 mg capsule) orally in fasted condition. | 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. |
| Period Title: Overall Study | ||
| STARTED | 10 | 12 |
| COMPLETED | 10 | 12 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat | Total |
|---|---|---|---|
| Arm/Group Description | 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. | 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. | Total of all reporting groups |
| Overall Participants | 10 | 12 | 22 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
63.0
(12.9)
|
64.4
(10.0)
|
63.8
(11.1)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
5
50%
|
8
66.7%
|
13
59.1%
|
| Male |
5
50%
|
4
33.3%
|
9
40.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
10
100%
|
12
100%
|
22
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
1
10%
|
0
0%
|
1
4.5%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
1
8.3%
|
1
4.5%
|
| White |
9
90%
|
11
91.7%
|
20
90.9%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Estimated Glomerular Filtration Rate (mL/min/1.73m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mL/min/1.73m^2] |
45.22
(8.54)
|
24.39
(3.31)
|
33.86
(12.23)
|
Outcome Measures
| Title | Number of Participants With Treatment-emergent Adverse Events (TEAEs) |
|---|---|
| Description | 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. |
| Time Frame | Up to Day 8 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Intent-to-treat (ITT) population: all enrolled participants who received a dose of the study drug. |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Count of Participants [Participants] |
6
60%
|
2
16.7%
|
| Title | Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values |
|---|---|
| Description | Parameters assessed for laboratory values included hematology, chemistry, urinalysis, and coagulation. The investigator was responsible for reviewing laboratory results for clinically significant changes. |
| Time Frame | Up to Day 8 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Urinalysis |
0
0%
|
0
0%
|
| Hematology |
0
0%
|
0
0%
|
| Serum chemistry |
1
10%
|
0
0%
|
| Coagulation |
0
0%
|
0
0%
|
| Title | Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Values |
|---|---|
| Description | 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. |
| Time Frame | Up to Day 8 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Count of Participants [Participants] |
2
20%
|
0
0%
|
| Title | Number of Participants With Clinically Abnormal 12-Lead Electrocardiogram (ECG) Findings |
|---|---|
| Description | 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. |
| Time Frame | Up to Day 2 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
| Title | Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Baseline PR interval |
178.8
(44.2)
|
182.5
(24.2)
|
| Change from Baseline at Day 2 PR interval |
-12.4
(28.4)
|
-3.5
(5.5)
|
| Baseline QRS interval |
98.8
(20.7)
|
97.7
(26.0)
|
| Change from Baseline at Day 2 QRS interval |
-0.8
(3.2)
|
0.0
(5.4)
|
| Baseline QT interval |
427.2
(22.0)
|
426.5
(39.7)
|
| Change from Baseline at Day 2 QT interval |
-13.8
(21.8)
|
-2.3
(16.7)
|
| Baseline QTc interval |
423.5
(22.8)
|
439.5
(35.8)
|
| Change from Baseline at Day 2 QTc interval |
3.1
(10.2)
|
2.0
(18.2)
|
| Title | Change From Baseline in Heart Rate |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Baseline |
59.8
(9.0)
|
64.3
(5.6)
|
| Change from Baseline at Day 2 |
5.2
(6.3)
|
1.8
(3.7)
|
| Title | Number of Participants With Clinically Significant Changes From Baseline in Physical Examination Findings |
|---|---|
| Description | 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. |
| Time Frame | Up to Day 8 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
| Title | Geometric Mean Maximum Observed Plasma Concentration (Cmax) of AKB-6548 |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic (PK) Evaluable Population: all ITT participants who had adequate and reliable PK data for the evaluation of PK of AKB-6548 plasma concentrations. |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [Micrograms per millilitre (mcg/mL)] |
42.486
(36.314)
|
40.952
(35.022)
|
| Title | Median Time to Reach Cmax (Tmax) of AKB-6548 |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Median (Full Range) [Hours] |
5.5
|
5.0
|
| Title | Mean Terminal Elimination Rate Constant (λz) |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Mean (Standard Deviation) [1/Hour] |
0.105
(0.029)
|
0.086
(0.020)
|
| Title | Median Terminal Elimination Half-life (T½) |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Median (Full Range) [Hours] |
7.070
|
7.530
|
| Title | Geometric Mean Area Under the Plasma Concentration-time Curve From 0 to Time T Over a Dosing Interval (AUC[0-T]) |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [mcg*hr/mL] |
441.651
(36.162)
|
448.399
(34.081)
|
| Title | Geometric Mean Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [mcg*hr/mL] |
503.688
(41.671)
|
535.813
(40.320)
|
| Title | Geometric Mean Apparent Oral Clearance (CL/F) |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [Litre per Hour (L/hr)] |
0.995
(41.683)
|
0.934
(40.324)
|
| Title | Geometric Mean Apparent Volume of Distribution During the Terminal Phase (Vd/F) |
|---|---|
| Description | 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. |
| Time Frame | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose (Day 2) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PK Evaluable Population |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [Liter] |
9.863
(20.479)
|
11.105
(31.747)
|
| Title | Change From Baseline in Mean Erythropoietin (EPO) |
|---|---|
| Description | The change from baseline was calculated by subtracting the baseline value from the individual post-dose visit values. |
| Time Frame | Baseline; 8, 12, and 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT Population. Overall number of participants analyzed represents participants with valid EPO measurements at both baseline and the post-dose hour. |
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 10 | 12 |
| Baseline |
23.14
(15.00)
|
21.65
(15.84)
|
| 8 Hours Post-dose |
6.16
(9.97)
|
12.07
(11.13)
|
| 12 Hours Post-dose |
5.41
(7.66)
|
11.09
(8.71)
|
| 24 Hours Post-dose |
-1.44
(5.71)
|
2.08
(5.57)
|
| Title | Exploratory: Change From Baseline in Hepcidin at 24 Hours |
|---|---|
| Description | |
| Time Frame | Baseline; 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Exploratory: Change From Baseline in Vascular Endothelial Growth Factor (VEGF) at 24 Hours |
|---|---|
| Description | |
| Time Frame | Baseline; 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Exploratory: Change From Baseline in Transferrin at 24 Hours |
|---|---|
| Description | |
| Time Frame | Baseline; 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Exploratory: Change From Baseline in Cystatin-C at 24 Hours |
|---|---|
| Description | |
| Time Frame | Baseline; 24 hours post -dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Exploratory: Change From Baseline in Adiponectin at 24 Hours |
|---|---|
| Description | |
| Time Frame | Baseline; 24 hours post -dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Exploratory: Change From Baseline in Ferritin at 24 Hours |
|---|---|
| Description | |
| Time Frame | Baseline; 24 hours post-dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | Up to Day 8 | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) on or after the first dose through each participant's last participation date, were reported. | |||
| Arm/Group Title | Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat | ||
| Arm/Group Description | 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. | 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. | ||
All Cause Mortality |
||||
| Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/12 (0%) | ||
Serious Adverse Events |
||||
| Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/12 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Cohort 1: CKD Stage 3 Vadadustat | Cohort 2: CKD Stage 4 Vadadustat | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/10 (60%) | 2/12 (16.7%) | ||
| Cardiac disorders | ||||
| Tachycardia | 1/10 (10%) | 0/12 (0%) | ||
| Gastrointestinal disorders | ||||
| Nausea | 2/10 (20%) | 0/12 (0%) | ||
| Vomiting | 1/10 (10%) | 0/12 (0%) | ||
| General disorders | ||||
| Catheter Site Inflammation | 0/10 (0%) | 1/12 (8.3%) | ||
| Pyrexia | 1/10 (10%) | 0/12 (0%) | ||
| Infections and infestations | ||||
| Upper Respiratory Tract Infection | 1/10 (10%) | 0/12 (0%) | ||
| Metabolism and nutrition disorders | ||||
| Hypomagnesaemia | 1/10 (10%) | 0/12 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 0/10 (0%) | 1/12 (8.3%) | ||
| Myalgia | 1/10 (10%) | 0/12 (0%) | ||
| Pain in Extremity | 1/10 (10%) | 0/12 (0%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Skin Papilloma | 1/10 (10%) | 0/12 (0%) | ||
| Nervous system disorders | ||||
| Headache | 1/10 (10%) | 0/12 (0%) | ||
| Somnolence | 0/10 (0%) | 1/12 (8.3%) | ||
| Tremor | 1/10 (10%) | 0/12 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Oropharyngeal pain | 0/10 (0%) | 1/12 (8.3%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Cold Sweat | 1/10 (10%) | 0/12 (0%) | ||
| Vascular disorders | ||||
| Hypotension | 1/10 (10%) | 0/12 (0%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Akebia Therapeutics |
|---|---|
| Organization | Akebia Therapeutics |
| Phone | 617-844-6128 |
| trials@akebia.com |
- AKB-6548-CI-0003