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)

Sponsor

Akebia Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT04313153

Collaborator

Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)

319

Enrollment

Locations

Arms

24.8

Actual Duration (Months)

5.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia	Drug: Vadadustat Drug: Darbepoetin alfa	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

319 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Masking Description:

This is an open-label, Sponsor-blind study.

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

May 27, 2020

Actual Primary Completion Date :

Nov 26, 2021

Actual Study Completion Date :

Jun 22, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vadadustat once daily	Drug: Vadadustat oral tablets
Experimental: Vadadustat three times weekly	Drug: Vadadustat oral tablets
Active Comparator: Darbepoetin alfa	Drug: Darbepoetin alfa intravenous or subcutaneous solution

Arm

Intervention/Treatment

Experimental: Vadadustat once daily

Drug: Vadadustat

oral tablets

Experimental: Vadadustat three times weekly

Drug: Vadadustat

oral tablets

Active Comparator: Darbepoetin alfa

Drug: Darbepoetin alfa

intravenous or subcutaneous solution

Outcome Measures

Primary Outcome Measures

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

Change in Hb value between Baseline and the secondary evaluation period (average Hb from Weeks 46 to 52) [Baseline; Weeks 46 to 52]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chula Vista	California	United States	91910
2	Research Site	Granada Hills	California	United States	91344
3	Research Site	Los Angeles	California	United States	90022
4	Research Site	Lynwood	California	United States	90262
5	Research Site	Northridge	California	United States	91324
6	Research Site	San Dimas	California	United States	91773
7	Research Site	Whittier	California	United States	90603
8	Research Site	Denver	Colorado	United States	80230
9	Research Site	Middlebury	Connecticut	United States	06762
10	Research Site	Coral Gables	Florida	United States	33134
11	Research Site	Tampa	Florida	United States	33614
12	Research Site	Winter Park	Florida	United States	32789
13	Research Site	Pontiac	Michigan	United States	48341
14	Research Site	Roseville	Michigan	United States	48066
15	Research Site	Minneapolis	Minnesota	United States	55404
16	Research Site	Brookhaven	Mississippi	United States	39601
17	Research Site	Tupelo	Mississippi	United States	38801
18	Research Site	Kansas City	Missouri	United States	64111
19	Research Site	Saint Louis	Missouri	United States	63136
20	Research Site	Las Vegas	Nevada	United States	89128
21	Research Site	Albuquerque	New Mexico	United States	87109
22	Research Site	Durham	North Carolina	United States	27704
23	Research Site	Kinston	North Carolina	United States	28504
24	Research Site	New Bern	North Carolina	United States	28562
25	Research Site	Bethlehem	Pennsylvania	United States	18017
26	Research Site	Orangeburg	South Carolina	United States	29118
27	Research Site	Chattanooga	Tennessee	United States	37404
28	Research Site	Knoxville	Tennessee	United States	37920
29	Research Site	Knoxville	Tennessee	United States	37923
30	Research Site	Austin	Texas	United States	78751
31	Research Site	Austin	Texas	United States	78758
32	Research Site	El Paso	Texas	United States	79902
33	Research Site	Houston	Texas	United States	77004
34	Research Site	Houston	Texas	United States	77099
35	Research Site	McAllen	Texas	United States	78503
36	Research Site	San Antonio	Texas	United States	78204
37	Research Site	San Antonio	Texas	United States	78212
38	Research Site	San Antonio	Texas	United States	78229
39	Research Site	Hampton	Virginia	United States	23666
40	Research Site	Mariánské Lázně		Czechia
41	Research Site	Nový Jičín		Czechia
42	Research Site	Plzen		Czechia
43	Research Site	Praha 9		Czechia
44	Research Site	Příbram		Czechia
45	Research Site	Slaný		Czechia
46	Research Site	Baja		Hungary
47	Research Site	Debrecen		Hungary
48	Research Site	Kaposvar		Hungary
49	Research Site	Kecskemét		Hungary
50	Research Site	Pécs		Hungary
51	Research Site	Pavia		Italy
52	Research Site	Vicenza		Italy
53	Research Site	Biała Podlaska		Poland
54	Research Site	Brodnica		Poland
55	Research Site	Lodz		Poland
56	Research Site	Pszczyna		Poland
57	Research Site	Sochaczew		Poland
58	Research Site #2	Barcelona		Spain
59	Research Site	Valencia		Spain