Back to resultsStudy to Assess the Safety and Pharmacokinetics of AKB-6548 in Participants With Chronic Kidney Disease (CKD), Stages 3 and 4
Primary Purpose
Chronic Kidney Disease
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Vadadustat
Sponsored by
About this trial
This is an interventional treatment trial for Chronic Kidney Disease focused on measuring CKD, CKD, Stage 3, CKD, Stage 4, Vadadustat, pharmacokinetics
Eligibility 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
Sites / Locations
- Research Site
- Research Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
CKD, Stage 3
CKD, Stage 4
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04707573
Brief Title
Study to Assess the Safety and Pharmacokinetics of AKB-6548 in Participants With Chronic Kidney Disease (CKD), Stages 3 and 4
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
July 8, 2010 (Actual)
Primary Completion Date
September 24, 2010 (Actual)
Study Completion Date
September 24, 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Akebia Therapeutics
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Disease
Keywords
CKD, CKD, Stage 3, CKD, Stage 4, Vadadustat, pharmacokinetics
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
CKD, Stage 3
Arm Type
Experimental
Arm Description
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.
Arm Title
CKD, Stage 4
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Vadadustat
Other Intervention Name(s)
AKB-6548
Intervention Description
oral capsules
Primary Outcome Measure Information:
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
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
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
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
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
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
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
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)
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)
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)
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)
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)
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)
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)
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)
Secondary Outcome Measure Information:
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
Other Pre-specified Outcome Measures:
Title
Exploratory: Change From Baseline in Hepcidin at 24 Hours
Time Frame
Baseline; 24 hours post-dose
Title
Exploratory: Change From Baseline in Vascular Endothelial Growth Factor (VEGF) at 24 Hours
Time Frame
Baseline; 24 hours post-dose
Title
Exploratory: Change From Baseline in Transferrin at 24 Hours
Time Frame
Baseline; 24 hours post-dose
Title
Exploratory: Change From Baseline in Cystatin-C at 24 Hours
Time Frame
Baseline; 24 hours post -dose
Title
Exploratory: Change From Baseline in Adiponectin at 24 Hours
Time Frame
Baseline; 24 hours post -dose
Title
Exploratory: Change From Baseline in Ferritin at 24 Hours
Time Frame
Baseline; 24 hours post-dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chief Medical Officer
Organizational Affiliation
Akebia Therapeutics Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55114
Country
United States
Facility Name
Research Site
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37920
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Study to Assess the Safety and Pharmacokinetics of AKB-6548 in Participants With Chronic Kidney Disease (CKD), Stages 3 and 4
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