42-Day Repeat Oral Dose Study of AKB-6548 in Participants With Chronic Kidney Disease and Anemia

• ClinicalTrials.gov Identifier: NCT01381094
• Recruitment Status: Completed
• First Posted: June 27, 2011
• Results First Posted: July 1, 2022
• Last Update Posted: July 1, 2022
• Sponsor: Akebia Therapeutics
• Information provided by (Responsible Party): Akebia Therapeutics

Study Description

Brief Summary:

The purpose of this study is to evaluate the dose response (efficacy), pharmacodynamic response, pharmacokinetics, safety, and tolerability of orally administered AKB-6548 in pre-dialysis participants with anemia with repeat dosing for 42 days.

Condition or disease	Intervention/treatment	Phase
Anemia; Kidney Disease	Drug: AKB-6548; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase 2a Randomized, Double-Blind, Placebo-Controlled, Dose Range Study to Assess the Pharmacodynamic Response, Pharmacokinetics, Safety, and Tolerability of 42-Day Repeat Oral Doses of AKB-6548 in Subjects With Anemia Secondary to Chronic Kidney Disease (CKD), Stages 3 and 4
• Actual Study Start Date: June 15, 2011
• Actual Primary Completion Date: February 16, 2012
• Actual Study Completion Date: February 16, 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: AKB-6548 240 mg	Drug: AKB-6548; oral dose administered once daily for 42 days
Experimental: AKB-6548 370 mg	Drug: AKB-6548; oral dose administered once daily for 42 days
Experimental: AKB-6548 500 mg	Drug: AKB-6548; oral dose administered once daily for 42 days
Experimental: AKB-6548 630 mg	Drug: AKB-6548; oral dose administered once daily for 42 days
Placebo Comparator: Placebo	Drug: Placebo; oral Placebo administered once daily for 42 days

Outcome Measures

Primary Outcome Measures :

1. Absolute Change From Baseline in Hemoglobin (Hgb) to End of Treatment (Week 6) [ Time Frame: Baseline, Week 6 ]
   Absolute change from Baseline was calculated as the Week 6 (end of treatment) value minus the Baseline value. Baseline Hgb was defined as the average of the last two measurements obtained prior to dosing. If there was only one measurement prior to dosing, this measurement served as Baseline. A positive change from Baseline indicated that hemoglobin concentration increased.

Secondary Outcome Measures :

1. Change From Baseline in Hgb at Week 1, Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
   Change from Baseline was calculated as the visit value minus the Baseline value. Baseline Hgb was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated that hemoglobin concentration increased.
2. Change From Baseline in Hematocrit (HCT) at Week 1, Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
   Change from Baseline was calculated as the visit value minus the Baseline value. Baseline HCT was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated HCT concentration increased.
3. Change From Baseline in Red Blood Cell (RBC) Count at Week 1, Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
   Change from Baseline was calculated as the visit value minus the Baseline value. Baseline RBC count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated RBC count increased.
4. Change From Baseline in Absolute Reticulocyte Count at Week 1, Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
   Change from Baseline was calculated as the visit value minus the Baseline value. Baseline Reticulocyte count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated reticulocyte count increased.
5. Change From Baseline in Reticulocyte Hgb Content at Week 6 [ Time Frame: Baseline, Week 6 ]
   Change from Baseline was calculated as the Week 6 value minus the Baseline value. Baseline Reticulocyte count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated reticulocyte Hgb content increased.
6. Maximum Change From Baseline in Hgb [ Time Frame: Baseline; up to Week 8 ]
   Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline Hgb was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated that hemoglobin concentration increased.
7. Maximum Change From Baseline in HCT [ Time Frame: Baseline; up to Week 8 ]
   Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline HCT was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated that HCT concentration increased.
8. Maximum Change From Baseline in RBC Count [ Time Frame: Baseline; up to Week 8 ]
   Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline RBC Count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated that RBC count increased.
9. Maximum Change in Absolute Reticulocyte Count From Baseline [ Time Frame: Baseline; up to Week 8 ]
   Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline absolute reticulocyte count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline. A positive change from Baseline indicated that reticulocyte count increased.
10. Number of Participants With Absolute Change From Baseline in Hgb ≥ 0.4, 0.6, 0.8, and 1.0 g/dL at the End of Dosing Period [ Time Frame: Up to Week 6 (End of the Dosing Period) ]
    Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline Hgb was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
11. Number of Participants With Change From Baseline in Hgb ≥5.0, 7.5, and 10.0% by the End of Dosing Period [ Time Frame: Up to Week 6 (End of The Dosing Period) ]
    Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline Hgb was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
12. Number of Participants With Change From Baseline in HCT ≥5.0, 7.5, and 10.0% by the End of Dosing Period [ Time Frame: Up to Week 6 (End of The Dosing Period) ]
    Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline HCT was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
13. Number of Participants With Change From Baseline in RBC Count ≥5.0, 7.5, and 10.0% by the End of Dosing Period [ Time Frame: Up to Week 6 (End of The Dosing Period) ]
    Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline RBC Count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
14. Number of Participants With Change From Baseline in Reticulocyte Count ≥6000, 12000, and 18000 Cells/uL by the End of Dosing Period [ Time Frame: Up to Week 6 (End of The Dosing Period) ]
    Change from Baseline was calculated as the maximum value minus the Baseline value. Baseline reticulocytes count was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
15. Change From Baseline in Total Iron at Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
    Change from Baseline was calculated as the visit value minus the Baseline value. Baseline total iron was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
16. Change From Baseline in Unsaturated Iron Binding Capacity at Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
    Change from Baseline was calculated as the visit value minus the Baseline value. Baseline Unsaturated Iron Binding Capacity was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
17. Change From Baseline in Iron Saturation at Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
    Change from Baseline was calculated as the visit value minus the Baseline value. Baseline iron saturation was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
18. Change From Baseline in Total Iron Binding Capacity (TIBC) at Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Follow-up Visit (up to Week 8) ]
    Change from Baseline was calculated as the visit value minus the Baseline value. Baseline TIBC was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
19. Change From Baseline in Ferritin at Week 2, Week 4, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 2, Week 4, Week 6, Follow-up (up to Week 8) ]
    Change from Baseline was calculated as the visit value minus the Baseline value. Baseline ferritin was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
20. Change From Baseline in Erythropoietin at Week 2, Week 6, and Follow-up Visit (up to Week 8) [ Time Frame: Baseline, Week 2, Week 6, Follow-up Visit (up to Week 8) ]
    Change from Baseline was calculated as the visit value minus the Baseline value. Baseline erythropoietin was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
21. Change From Baseline in Hepcidin at Week 6 [ Time Frame: Baseline, Week 6 ]
    Change from Baseline was calculated as the Week 6 value minus the Baseline value. Baseline hepcidin was defined as the average of the last two measurements obtained prior to dosing; if there was only one value prior to dosing, this value served as Baseline.
22. Mean Plasma Vadadustat Concentrations on Week 2 and Week 4 [ Time Frame: Week 2: Pre-dose and post-dose; Week 4: Pre-dose ]
    Plasma samples were collected for the analysis.
23. Mean Plasma Vadadustat Acyl-Glucuronide Concentrations on Week 2 and Week 4 [ Time Frame: Week 2: Pre-dose; Week 4: Pre-dose ]
    Plasma samples were collected for the analysis.
24. Number of Participants Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 8 (Follow-up Visit 2 weeks after last dose) ]
    An adverse event (AE) was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. A TEAE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. A SAE included AEs that met one or more of the following criteria/outcomes: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, and congenital anomaly/birth defect.
25. Number of Participants With Clinically Significant Changes From Baseline in Vital Signs Parameter [ Time Frame: Up to Week 8 (Follow-up Visit 2 weeks after last dose) ]
    Parameters assessed for vital signs included sitting blood pressure, pulse, respiratory rate, and body temperature. The investigator was responsible for reviewing laboratory results for clinically significant changes.
26. Number of Participants With Clinically Significant Abnormal 12-Electrocardiogram (ECG) Findings [ Time Frame: Up to Week 8 (Follow-up Visit 2 weeks after last dose) ]
    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. Clinical significance is determined by the investigator. The investigator was responsible for reviewing laboratory results for clinical significance.
27. Mean Change From Baseline in PR Interval, QT Interval, QRS Interval, and QT Corrected (QTc) Interval [ Time Frame: Baseline, Week 6 ]
    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).
28. Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values [ Time Frame: Up to Week 8 (Follow-up Visit 2 weeks after last dose) ]
    Parameters assessed for laboratory values included hematology, serum chemistry, C-reactive protein, DHEA-S, VEGF, and cystatin C. The investigator was responsible for reviewing laboratory results for clinically significant changes.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 79 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

• 18 to 79 years of age, inclusive
• Chronic Kidney Disease (eGFR <60 mL/min), not yet on dialysis
• Hemoglobin (Hgb) ≤ 10.5 g/dL
• Transferring saturation ≥ 20%
• Ferritin ≥ 50 ng/mL

Key Exclusion Criteria:

• Body mass index >42
• Red blood cell transfusion within 12 weeks
• Androgen therapy within the previous 21 days prior to study dosing
• Therapy with any approved or experimental erythropoiesis stimulating agent (ESA) within the 11 weeks prior to the Screening visit
• Participants meeting the criteria of ESA resistance within the previous 4 months
• Individual doses of intravenous iron of greater than 250 mg within the past 21 days
• Aspartate aminotransferase or alanine aminotransferase >1.8x upper limit of normal (ULN)
• Alkaline phosphatase >2x ULN
• Total bilirubin >1.5x ULN
• Uncontrolled hypertension
• New York Heart Association Class III or IV congestive heart failure
• Myocardial infarction, acute coronary syndrome, or stroke within 6 months prior to dosing

Contacts and Locations

Locations

United States, Arkansas

Pine Bluff, Arkansas, United States

United States, California

Covina, California, United States

Los Angeles, California, United States

Lynwood, California, United States

Riverside, California, United States

San Dimas, California, United States

Whittier, California, United States

United States, Florida

Coral Springs, Florida, United States

Lauderdale Lakes, Florida, United States

Miami, Florida, United States

Ocala, Florida, United States

United States, Georgia

Augusta, Georgia, United States

Macon, Georgia, United States

United States, Kansas

Wichita, Kansas, United States

United States, Louisiana

Shreveport, Louisiana, United States

United States, Massachusetts

Springfield, Massachusetts, United States

United States, Michigan

Detroit, Michigan, United States

Pontiac, Michigan, United States

Warren, Michigan, United States

United States, New York

Bethpage, New York, United States

Mineola, New York, United States

United States, North Carolina

Wilmington, North Carolina, United States

United States, Oklahoma

Oklahoma City, Oklahoma, United States

United States, Tennessee

Knoxville, Tennessee, United States

United States, Texas

Austin, Texas, United States

Fort Worth, Texas, United States

Houston, Texas, United States

San Antonio, Texas, United States

Sponsors and Collaborators

Akebia Therapeutics

Investigators

• Study Director: Chief Medical Officer; Akebia Therapeutics Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.

Martin ER, Smith MT, Maroni BJ, Zuraw QC, deGoma EM. Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease. Am J Nephrol. 2017;45(5):380-388. doi: 10.1159/000464476. Epub 2017 Mar 25.

• Responsible Party: Akebia Therapeutics
• ClinicalTrials.gov Identifier: NCT01381094
• Other Study ID Numbers: AKB-6548-CI-0005
• First Posted: June 27, 2011
• Results First Posted: July 1, 2022
• Last Update Posted: July 1, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Akebia Therapeutics:

anemia; chronic kidney disease; CKD; chronic renal insufficiency; renal impairment; erythropoietin; safety; efficacy; tolerability; pharmacokinetics

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Hematologic Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes