Clinical trial NCT03799627: Study of Vadadustat in Hemodialysis Participants With Anemia Switching From Epoetin Alfa
Official title: Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment of Anemia in Hemodialysis Subjects Converting From Epoetin Alfa (FO2RWARD-2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anemia
Dialysis-dependent Chronic Kidney Disease
Keywords: Vadadustat
AKB-6548
Anemia
Chronic kidney disease (CKD)
erythropoietin
Lead sponsor: Akebia Therapeutics
Sponsor class: INDUSTRY
First posted: 2019-01-10
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Open-Label, Active-Controlled
Primary purpose: TREATMENT

Brief summary: This is a Phase 2 open-label efficacy, safety, and pharmacokinetic/pharmacodynamic (PK/PD) study to evaluate oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy.

Detailed description: This is a Phase 2, randomized, open-label study to evaluate efficacy and safety of oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy. The study will be conducted in two parts running in parallel: Part 1, Main Study in a hemodialysis population on maintenance treatment with Epoetin Alfa; Part 2 is in a hemodialysis population that are erythropoiesis-stimulating agent (ESA) hyporesponders on maintenance treatment with Epoetin Alfa. For all participants (Main and ESA hyporesponder parallel study), the study will include a Screening Period, a Treatment Period, and a Safety Follow-Up Period. PK and PD sampling will be done throughout the study. The aim is to achieve and maintain hemoglobin (Hb) levels within the target range of 10.0 to 11.0 grams per deciliter (g/dL), inclusive, while targeting the middle of the range and minimizing excursions outside the target range.

Eligibility criteria: Inclusion Criteria:

* ≥18 years of age, providing informed consent
* Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal disease for at least 12 weeks prior to Screening
* Maintained on intravenous Epoetin Alfa therapy for 8 weeks prior to and including Screening through Screening Visit 2 (SV2)
* Eligibility in the Main study and erythropoiesis-stimulating agent (ESA) hyporesponder parallel study is based on the following mean weekly Epoetin Alfa doses:

  1. Main study: Mean weekly Epoetin Alfa dose \<300 Units per kilogram per week (U/kg/week) for 8 weeks prior to SV2;
  2. ESA hyporesponder parallel study: Mean weekly Epoetin Alfa dose ≥300 U/kg/week for 8 weeks prior to SV2
* Two Hb values measured by the central laboratory at least 4 days apart between Screening Visit 1 (SV1) and SV2 as indicated:.

  1. Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive;
  2. ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 grams per deciliter (g/dL), inclusive
* Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20% during Screening
* Folate and vitamin B12 measurements ≥ lower limit of normal during Screening
* Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent historical measurement within 8 weeks prior to or during Screening
* Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure

Exclusion Criteria:

* Anemia due to a cause other than chronic kidney disease (e.g., sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia)
* Active bleeding or recent blood loss within 8 weeks prior to randomization
* Red blood cell (RBC) transfusion within 8 weeks prior to randomization
* Anticipated to discontinue hemodialysis during the study
* Judged by the Investigator that the participant is likely to need rescue therapy (ESA administration or RBC transfusion) immediately after enrollment in the study
* History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver)
* Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin \>1.5 x upper limit of normal (ULN) during Screening. Participants with a history of Gilbert's syndrome are not excluded.
* Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of Epoetin Alfa
* Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), surgical or percutaneous intervention for coronary, cerebrovascular or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalization for heart failure (HF) or New York Heart Association Class IV HF, or stroke within 12 weeks prior to or during Screening
* History of new or recurrent malignancy within 2 years prior to and during Screening or currently receiving treatment or suppressive therapy for cancer. Participants with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical carcinoma in situ are not excluded.
* History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during Screening
* History of hemosiderosis or hemochromatosis
* History of prior organ transplantation (participants with a history of failed kidney transplant or corneal transplants are not excluded)
* Scheduled organ transplant from a living donor and participants on the kidney transplant wait-list who are expected to receive a transplant within 6 months
* History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded)
* Known hypersensitivity to Vadadustat, Epoetin Alfa, or any of their excipients
* Any prior use of a hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitor or any use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to randomization
* For female participants of non-childbearing potential:

  1. inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy) at least 1 month prior to Screening;
  2. not considered post-menopausal (no menses for \>1 year with follicle stimulating hormone \>40 U/Liter at Screening)
* For female participants of childbearing potential:

  1. lack of confirmation of the use of acceptable forms of contraception\* for a minimum of one complete menstrual cycle prior to Screening;
  2. positive serum pregnancy test at SV2;
  3. unwilling to use two acceptable forms of contraception\* (at least one of which must be a barrier method) starting Baseline/Day 1, throughout the Treatment Period and for 30 days after the final study drug administration
* Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the final study drug administration
* Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after the final study drug administration
* Male participants who have not had a vasectomy and do not agree to the following: use of an acceptable form of contraception\* during the study and for 30 days after the last dose of the study drug; to not donate semen during the study and for at least 30 days after the last dose of Vadadustat
* Participants with bilateral native nephrectomy
* Any other reason, which in the opinion of the Investigator, would make the participant not suitable for participation in the study

  * Acceptable forms of contraception include:

    * Established use of oral, injected or implanted hormonal methods of contraception;
    * Placement of an intrauterine device or intrauterine system;
    * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

Primary outcomes:
measure: Mean Change in Hemoglobin (Hb) Between Baseline and the Primary Evaluation Period (PEP)
timeFrame: Baseline; Week 10 to Week 12
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to Week 24
measure: Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameter Values
timeFrame: Up to Week 24
measure: Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Values
timeFrame: Up to Week 24
measure: Number of Participants Classified as Hb Outliers
timeFrame: Weeks 13 - 20
Secondary outcomes:
measure: Number of Participants With Hb Values Within the Target Range at the PEP
timeFrame: Week 10 to Week 12
measure: Mean Change in Hb From the PEP to the Secondary Evaluation Period (SEP) in Participants Who Transitioned to Three Times Per Week (TIW) Vadadustat Dosing After Week 12
timeFrame: Week 10 to Week 12; Week 18 to Week 20
measure: Mean Change in Hb Between Baseline and the SEP
timeFrame: Baseline; Week 18 to Week 20
measure: Number of Participants With Hb Values Within the Target Range at the SEP
timeFrame: Week 18 to Week 20
measure: Number of Participants With Hb Values Within the Target Range at the SEP in Participants Who Transitioned to TIW Vadadustat Dosing
timeFrame: Week 18 to Week 20
measure: Number of Participants With a Mean Increase in Hb From Baseline to the PEP ≥0.5 g/dL or With Hb Values Within the Target Range at the PEP
timeFrame: Week 10 to Week 12
measure: Number of Participants With a Mean Increase in Hb From Baseline to the SEP ≥0.5 g/dL or With Hb Values Within the Target Range at the SEP
timeFrame: Week 18 to Week 20
measure: Number of Participants Requiring at Least One Intravenous (IV) Elemental Iron Supplementation
timeFrame: Up to Week 20
measure: Number of Participants Requiring Erythropoiesis-stimulating Agent (ESA) Rescue
timeFrame: Up to Week 20
measure: Number of Participants Requiring Red Blood Cell (RBC) Transfusion
timeFrame: Up to Week 20
measure: Mean Serum Concentration of Erythropoietin (EPO) for Vadadustat Treatment Groups by Strata of Epoetin Alfa Dose Group
timeFrame: Baseline; Week 1 (pre-dose), Week 1 +1 (Day 8; pre-dose), Week 11 (pre-dose), and Week 13 (pre-dose)
measure: Mean Change From Baseline in Reticulocyte Count
timeFrame: Baseline; Week 1, Week 4, Week 8, Week 11, Week 12, Week 13, Week 16, and Week 20
measure: Mean Change From Baseline in Iron Concentration
timeFrame: Baseline; Week 4, Week 8, Week 12, Week 16, and Week 20
measure: Mean Change From Baseline in Ferritin Concentration
timeFrame: Baseline; Week 4, Week 8, Week 12, Week 16, and Week 20
measure: Mean Change From Baseline in Total Iron Binding Capacity
timeFrame: Baseline; Week 4, Week 8, Week 12, Week 16, and Week 20
measure: Mean Change From Baseline in Hepcidin Concentration
timeFrame: Baseline; Week 12 and Week 20
measure: Geometric Mean Maximum Observed Plasma Concentration (Cmax) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
measure: Geometric Mean Area Under the Concentration-time Curve (AUC) From Time 0 to 24 Hours (AUC0-24) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11: pre-dose, 2h, 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
measure: Median Terminal Half-life (t1/2) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
measure: Median Time to Reach Cmax (Tmax) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
measure: Geometric Mean Elimination Rate Constant (λz) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11, Week 13: pre-dose, 2 hours (h), 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
measure: Geometric Mean Apparent Total Body Clearance (CLss/F) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11: pre-dose, 2h, 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
measure: Geometric Mean Apparent Volume of Distribution (Vz/F) of Vadadustat Following a Single Dose
timeFrame: Day 1; Week 1, Week 1 +1 (Day 8), Week 11: pre-dose, 2h, 3.5h, and 5h post-dose, and additionally at 7h and 10.5h post-dose
Other outcomes:
Locations:
city: Fresno
country: United States
facility: Research Site
state: California
city: Granada Hills
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Northridge
country: United States
facility: Research Site
state: California
city: Riverside
country: United States
facility: Research Site
state: California
city: San Dimas
country: United States
facility: Research Site #1
state: California
city: San Dimas
country: United States
facility: Research Site #2
state: California
city: San Gabriel
country: United States
facility: Research Site
state: California
city: Tarzana
country: United States
facility: Research Site
state: California
city: Vacaville
country: United States
facility: Research Site
state: California
city: Victorville
country: United States
facility: Research Site
state: California
city: Denver
country: United States
facility: Research Site
state: Colorado
city: Bridgeport
country: United States
facility: Research Site
state: Connecticut
city: Hartford
country: United States
facility: Research Site
state: Connecticut
city: Coral Gables
country: United States
facility: Research Site
state: Florida
city: Hollywood
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Winter Park
country: United States
facility: Research Site
state: Florida
city: Augusta
country: United States
facility: Research Site
state: Georgia
city: Statesboro
country: United States
facility: Research Site
state: Georgia
city: Roseville
country: United States
facility: Research Site
state: Michigan
city: Minneapolis
country: United States
facility: Research Site #1
state: Minnesota
city: Minneapolis
country: United States
facility: Research Site #2
state: Minnesota
city: Kansas City
country: United States
facility: Research Site
state: Missouri
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Bronx
country: United States
facility: Research Site
state: New York
city: Asheville
country: United States
facility: Research Site
state: North Carolina
city: Wilmington
country: United States
facility: Research Site
state: North Carolina
city: Canton
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: El Paso
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Chesapeake
country: United States
facility: Research Site
state: Virginia
city: Norfolk
country: United States
facility: Research Site
state: Virginia
city: Wauwatosa
country: United States
facility: Research Site
state: Wisconsin
Study officials:
affiliation: Akebia Therapeutics Inc.
name: Chief Medical Officer
role: STUDY_DIRECTOR
References:
citation: 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.