Trial Evaluating the Efficacy and Safety of Oral Vadadustat Once Daily (QD) and Three Times Weekly (TIW) for the Maintenance Treatment of Anemia in Hemodialysis Subjects Converting From Erythropoiesis-Stimulating Agents (ESAs)

Study Overview
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Brief Summary
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This trial will be conducted to demonstrate the efficacy and safety of vadadustat compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis participants after conversion from current erythropoiesis-stimulating agent (ESA) therapy.

Detailed Description
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This study consists of three periods: Screening Period Conversion and Maintenance Treatment Period Safety Follow-up Period Individual participants will participate in total trial duration of approximately 64 weeks.

Official Title
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Phase 3b, Randomized, Open-label, Active-controlled Trial Evaluating the Efficacy and Safety of Oral Vadadustat Once Daily (QD) and Three Times Weekly (TIW) for the Maintenance Treatment of Anemia in Hemodialysis Subjects Converting From Erythropoiesis-Stimulating Agents (ESAs)

Conditions
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Anemia

Intervention / Treatment
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* Drug: Vadadustat
* Drug: Darbepoetin alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Receiving chronic, outpatient three times weekly (TIW) in-center hemodialysis for end-stage renal disease for at least 12 weeks prior to 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 Use of any approved erythropoiesis-stimulating agents (ESAs) for at least the 8 weeks prior to Screening Visit 2 Two hemoglobin (Hb) values, at least 4 days apart, measured by the central laboratory during Screening within the following prespecified ranges: Hb values between 8.0 and 11.0 grams per deciliter (g/dL) (inclusive) in the United States; Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe 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 Exclusion Criteria: Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product (IMP). If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, or birth control. 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 Women who are breast feeding and/or who have a positive pregnancy test result prior to receiving IMP Participants with contraindication to required trial assessment Participants who, is in opinion of the investigator or medical monitor, have a medical history or medical findings inconsistent with safety or trial compliance 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) Participants meeting cut-off of the following equivalent mean weekly doses calculated over 8 weeks prior to Screening Visit 2 Methoxy polyethylene glycol-epoetin beta > 50 micrograms (µg)/week; Darbepoetin alfa > 100 µg/week; Epoetin analogues > 23000 International Units (IU)/week Active bleeding or recent blood loss within 8 weeks prior to randomization Red blood cell transfusion within 8 weeks prior to randomization Anticipated to discontinue hemodialysis during the trial Judged by the investigator that the participant is likely to need rescue therapy (ESA administration or red blood cell [RBC] transfusion) immediately after enrollment in the trial 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 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 an ESA 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 a new or recurrent episode 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 subjects 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, darbepoetin alfa, or any of their excipients Use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to screening or during screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase inhibitor. Participants may participate in another concurrent trial only if that trial is a non-interventional, observational investigation. Participants with bilateral native nephrectomy Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration Any other reason, which in the opinion of the investigator, would make the participant not suitable for participation in the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vadadustat once daily (QD)<br> | Drug: Vadadustat<br>* oral tablets<br>|
| Experimental: Vadadustat three times weekly (TIW)<br> | Drug: Vadadustat<br>* oral tablets<br>|
| Active Comparator: Darbepoetin alfa<br> | Drug: Darbepoetin alfa<br>* intravenous or subcutaneous solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hemoglobin (Hb) between Baseline (average pretreatment Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, inclusive) |  | Baseline; Weeks 20 to 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hb value between Baseline and the secondary evaluation period (average Hb from Weeks 46 to 52) |  | Baseline; Weeks 46 to 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vadadustat, maintenance treatment, hemodialysis, erythropoiesis-stimulating agents, darbepoetin alfa