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

NCT04707573 | Completed Phase 2 Results FDA Drug

• 1 other identifier: AKB-6548-CI-0003
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

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.

Conditions

Chronic Kidney Disease

Keywords

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

Outcome Measures

Primary Outcomes (15)

• 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 Outcomes (1)

• Change From Baseline in Mean Erythropoietin (EPO)

  Baseline; 8, 12, and 24 hours post-dose

Other Outcomes (6)

• 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

Study Arms (2)

CKD, Stage 3

EXPERIMENTAL

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

CKD, Stage 4

EXPERIMENTAL

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

Interventions

Vadadustat DRUG

oral capsules

Also known as: AKB-6548

CKD, Stage 3; CKD, Stage 4

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Akebia Therapeutics: lead

Study Sites (2)

Research Site

Saint Paul, Minnesota, 55114, United States

Location

Research Site

Knoxville, Tennessee, 37920, United States

Location

MeSH Terms

Conditions

Renal Insufficiency, Chronic

Interventions

vadadustat

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Akebia Therapeutics
• Organization: Akebia Therapeutics

trials@akebia.com

617-844-6128

Study Officials

• Chief Medical Officer

  Akebia Therapeutics Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2020
• First Posted: January 13, 2021
• Study Start: July 8, 2010
• Primary Completion: September 24, 2010
• Study Completion: September 24, 2010
• Last Updated: June 28, 2022
• Results First Posted: May 17, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)