FO2RWARD-2: Study of Vadadustat in Hemodialysis Patients With Anemia Switching From Epoetin Alfa

• Sponsor: Akebia Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03799627
• Collaborator: (none)
• Enrollment: 175
• Locations: 41
• Arms: 3
• Actual Duration (Months): 17.4
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia; Dialysis-dependent Chronic Kidney Disease	Drug: Vadadustat; Drug: Epoetin Alfa; Drug: Vadadustat TIW	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 175 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, Open-Label, Active-ControlledRandomized, Open-Label, Active-Controlled
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Jan 31, 2019
• Actual Primary Completion Date: Jun 5, 2020
• Actual Study Completion Date: Jul 15, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vadadustat The initial dose of vadadustat (300, 450, or 600 milligrams [mg]) will be based upon the dose of epoetin alfa dose participants had received prior to vadadustat treatment	Drug: Vadadustat; Vadadustat Tablets 150 mg; Other Names: AKB-6548
Experimental: Vadadustat TIW Participants randomized to vadadustat (Main and erythropoiesis-stimulating agent [ESA] hyporesponder parallel studies) who complete a once-daily dosing regimen treatment period and meet eligibility criteria for transition to three times weekly (TIW) dosing will switch to TIW dosing	Drug: Vadadustat TIW; Oral vadadustat
Active Comparator: Epoetin alfa Epoetin alfa	Drug: Epoetin Alfa; Epoetin Alfa; Other Names: Procrit, Epogen

Outcome Measures

Primary Outcome Measures

1. Mean change in hemoglobin (Hb) between Baseline (average pretreatment Hb) and the primary evaluation period [Baseline; Week 10 to Week 12]

Secondary Outcome Measures

1. Proportion of participants with Hb values within the target range (10.0 to 11.0 grams per deciliter [g/dL], inclusive) at the primary evaluation period (Weeks 10 to 12) [Week 10 to Week 12]

2. For participants who transitioned to TIW vadadustat dosing, mean change in Hb from the primary evaluation period (average Hb from Week 10 to Week 12) to the secondary evaluation period (average Hb from Week 18 to Week 20) [Week 10 to Week 20]

3. Mean change in Hb between Baseline (average pretreatment Hb) and the secondary evaluation period (average Hb from Week 18 to Week 20) [Week 18 to Week 20]

4. Proportion of participants with Hb values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period (Week 18 to Week 20) [Week 18 to Week 20]

5. For participants who transitioned to TIW vadadustat dosing, proportion of participants with Hb values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period (Week 18 to Week 20) [Week 18 to Week 20]

6. Proportion of participants with a mean increase in Hb from Baseline to the primary evaluation period ≥0.5 g/dL (average Hb from Week 10 to Week 12) [Week 10 to Week 12]

7. Proportion of participants with Hb values within the target range (10.0 to 11.0 g/dL, inclusive) at the primary evaluation period (Week 10 to Week 12) [Week 10 to Week 12]

8. Proportion of participants with a mean increase in Hb from Baseline to the secondary evaluation period ≥0.5 g/dL (average Hb from Week 18 to Week 20) [Week 18 to Week 20]

9. Proportion of participants with Hb values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period (Week 18 to Week 20) [Up to 20 Weeks]

10. Number of participants requiring intravenous iron supplementation [Up to 28 Weeks]

11. Number of participants requiring erythropoiesis-stimulating agent (ESA) rescue [Up to 28 Weeks]

12. Number of participants requiring red blood cell (RBC) transfusion [Up to 28 Weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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; and 2;

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Fresno	California	United States	93720
2	Research Site	Granada Hills	California	United States	91344
3	Research Site	Los Angeles	California	United States	90022
4	Research Site	Northridge	California	United States	91324
5	Research Site	Riverside	California	United States	92501
6	Research Site #1	San Dimas	California	United States	91773
7	Research Site #2	San Dimas	California	United States	91773
8	Research Site	San Gabriel	California	United States	91776
9	Research Site	Tarzana	California	United States	91356
10	Research Site	Vacaville	California	United States	95688
11	Research Site	Victorville	California	United States	92394
12	Research Site	Denver	Colorado	United States	80230
13	Research Site	Bridgeport	Connecticut	United States	06606
14	Research Site	Hartford	Connecticut	United States	06762
15	Research Site	Coral Gables	Florida	United States	33134
16	Research Site	Hollywood	Florida	United States	33024
17	Research Site	Miami	Florida	United States	33126
18	Research Site	Miami	Florida	United States	33134
19	Research Site	Miami	Florida	United States	33150
20	Research Site	Tampa	Florida	United States	33607
21	Research Site	Tampa	Florida	United States	33614
22	Research Site	Winter Park	Florida	United States	32789
23	Research Site	Augusta	Georgia	United States	30909
24	Research Site	Statesboro	Georgia	United States	30458
25	Research Site	Roseville	Michigan	United States	48066
26	Research Site #1	Minneapolis	Minnesota	United States	55404
27	Research Site #2	Minneapolis	Minnesota	United States	55404
28	Research Site	Kansas City	Missouri	United States	64111
29	Research Site	Las Vegas	Nevada	United States	89107
30	Research Site	Bronx	New York	United States	10461
31	Research Site	Asheville	North Carolina	United States	28801
32	Research Site	Wilmington	North Carolina	United States	28401
33	Research Site	Canton	Ohio	United States	44718
34	Research Site	Oklahoma City	Oklahoma	United States	73116
35	Research Site	El Paso	Texas	United States	79915
36	Research Site	Houston	Texas	United States	77004
37	Research Site	San Antonio	Texas	United States	78229
38	Research Site	San Antonio	Texas	United States	78258
39	Research Site	Chesapeake	Virginia	United States	23320
40	Research Site	Norfolk	Virginia	United States	23510
41	Research Site	Wauwatosa	Wisconsin	United States	53226

Sponsors and Collaborators

• Akebia Therapeutics

Investigators

• Study Director: Akebia Therapeutics, Sponsor GmbH

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Akebia Therapeutics
• ClinicalTrials.gov Identifier: NCT03799627
• Other Study ID Numbers: AKB-6548-CI-0025
• First Posted: Jan 10, 2019
• Last Update Posted: Jun 11, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Akebia Therapeutics: Vadadustat; AKB-6548; Anemia; Chronic kidney disease (CKD); erythropoietin
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Epoetin Alfa; Glycine

Study Results

No Results Posted as of Jun 11, 2021