Study of Roxadustat (FG-4592) to Correct Anemia in Newly Initiated Dialysis Participants Not on Erythropoiesis-Stimulating Agent Treatment

Study Overview
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Brief Summary
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The purpose of this study is to evaluate efficacy and safety of roxadustat in the correction of anemia in participants with end-stage renal disease who recently started dialysis.

Detailed Description
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Participants on hemodialysis (HD) will be randomized to 3 treatment arms (A, B, and C) of in a 1:1:1 ratio to receive no iron supplementation, oral iron supplementation, and IV iron supplementation, respectively, in addition to roxadustat. At the same time, participants on peritoneal dialysis (PD) will be enrolled into Arm D. Arm E will enroll either HD or PD participants, and is an optional, confirmatory/supplemental treatment arm with flexible dosing and flexible iron supplementation based on the evaluation of data from the previous 4 treatment arms. Initial roxadustat dose will be based on a tiered, weight-based dosing scheme (low weight [40 to 60 kilograms {kg}], medium weight [>60 to 90 kg], and heavy weight [>90 to 140 kg] participants will receive 60, 100, and 140 milligrams [mg] roxadustat, respectively). Dose adjustments will be implemented (up to a maximum roxadustat dose of 140, 200, and 300 mg for low, medium, and high weight participants, respectively) during Weeks 5 and 9, depending on the hemoglobin (Hb) level and rate of Hb rise in the previous 4 weeks.

Official Title
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A Phase 2, Randomized, Open-Label, Dose Titration, Safety and Efficacy Study of FG-4592 for the Correction of Anemia in Newly Initiated Dialysis Patients Not on Erythropoiesis-Stimulating Agent Treatment

Conditions
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Dialysis, Anemia

Intervention / Treatment
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* Drug: Roxadustat
* Drug: Oral Iron
* Drug: IV Iron


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Receiving HD or PD for native kidney end-stage renal disease (ESRD) for 2 weeks to 4 months, prior to randomization Mean of the 2 most recent Hb values during the screening period, obtained at least 7 days apart, must be <10.0 grams (g)/deciliter (dL), with a difference of ≤1.0 g/dL between the 2 values Body weight 40 to 140 kilograms (kg) Exclusion Criteria: Previously received erythropoiesis-stimulating agents Received IV iron within 4 weeks of randomization Received red blood cell transfusion within 8 weeks prior to randomization or anticipated need for transfusion during the treatment period Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus antibody (anti-HCV Ab) History of chronic liver disease Clinically significant infection New York Heart Association Class III or IV congestive heart failure History of malignancy, except the following: cancers determined to be cured or in remission for ≥5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) even if it is currently in remission History of other blood disorders Active hemolysis or diagnosis of hemolytic syndrome Known bone marrow fibrosis Uncontrolled or symptomatic secondary hyperparathyroidism History of alcohol or drug abuse within a year prior to randomization, or anticipated inability to avoid consumption of more than 3 alcoholic beverages per day History of allergy or sensitivity to oral or IV iron therapy Seizure disorder or receiving anti-epilepsy medication for seizure disorder within 12 weeks prior to randomization Pregnant or breast-feeding females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Arm A + E (Participants on HD): Roxadustat Only, No Iron<br>Participants on HD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally 3 times weekly (TIW) for 12 weeks. | Drug: Roxadustat<br>* Tiered, weight-based dosing per schedule specified in the arm.<br>* Other names: FG-4592;|
| Experimental: Arm B (Participants on HD): PO Iron (Ferrous Fumarate or Ferrous Gluconate) Between 50 and 195 mg<br>Participants on HD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally TIW with iron (ferrous fumarate or ferrous gluconate) PO at doses containing elemental iron between 50 and 195 mg daily (depending on the type of iron formulation available in their countries) for 12 weeks. | Drug: Roxadustat<br>* Tiered, weight-based dosing per schedule specified in the arm.<br>* Other names: FG-4592;Drug: Oral Iron<br>* Administered per oral dose and schedule specified in the arm.<br>|
| Experimental: Arm C (Participants on HD): IV Iron (Ferric Gluconate Complex in Sucrose or Equivalent) 60 mg<br>Participants on HD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally TIW with approximately 60 mg IV iron (ferric gluconate complex in sucrose injection [for example, Ferrlecit®] or equivalent) once a week for 12 weeks. | Drug: Roxadustat<br>* Tiered, weight-based dosing per schedule specified in the arm.<br>* Other names: FG-4592;Drug: IV Iron<br>* Administered per IV dose and schedule specified in the arm.<br>|
| Experimental: Arm D (Participants on PD): PO Iron (Ferrous Fumarate or Ferrous Gluconate) Between 50 and 195 mg<br>Participants on PD will receive roxadustat capsules at the applicable dose (up to a maximum roxadustat dose of 140, 200, and 300 mg) based on weight and Hb level, administered orally TIW with iron (ferrous fumarate or ferrous gluconate) PO at doses containing elemental iron between 50 and 195 mg daily (depending on the type of iron formulation available in their countries) for 12 weeks. | Drug: Roxadustat<br>* Tiered, weight-based dosing per schedule specified in the arm.<br>* Other names: FG-4592;Drug: Oral Iron<br>* Administered per oral dose and schedule specified in the arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline in Hb During Weeks 3-13 | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. This outcome measure is derived from the maximum change from baseline during Weeks 3-13, without last observation carried forward (LOCF) imputation. | Baseline, Weeks 3-13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Hb During Weeks 2-5, 6-9, and 10-13 | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. | Baseline, Weeks 2-5, 6-9, and 10-13 | 
| Number of Participants Whose Maximum Hb Achieved During Treatment Was at Least 1.0 g/dL Increase From Baseline and Was ≥11.0 g/dL | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. | Week 3 to 13 | 
| Number of Participants Whose Maximum Hb Achieved During Treatment Was at Least 1.0 g/dL Increase From Baseline and Was ≥10.0 g/dL | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. | Week 3 to 13 | 
| Number of Participants With a Hb Response, Defined as an Increase in Hb by ≥1.0 g/dL From Baseline, by Weeks 5, 9, and 13 | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. | Weeks 5, 9, and 13 | 
| Number of Participants Who Achieved Maximum Hb During Weeks 3-13 |  | Weeks 3-13 | 
| Number of Participants With a Maximum Change From Baseline in Hb During Weeks 3-13 | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. The number of participants who fall within the following categories of maximum change are reported: <1 g/dL, ≥1 g/dL, 1 to <2 g/dL, 2 to <3 g/dL, >3 to <4 g/dL, ≥4 g/dL. | Baseline, Weeks 3-13 | 
| Median Time to Hb Response (Increase in Hb by ≥1.0 g/dL From Baseline) | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. | Baseline up to Week 13 | 
| Weekly Dose at First Hb Response (Increase in Hb by ≥1.0 g/dL From Baseline) | Baseline Hb was defined as the mean of the last 3 central laboratory Hb values prior to the first dose administration. | Baseline up to Week 13 | 
| Number of Participants Requiring Dose Increase at Weeks 5 and 9 | Number of participants requiring dose increase due to any reasons is reported. | Weeks 5 and 9 | 
| Number of Participants Requiring Dose Reduction or Dose Discontinuation Due to Excessive Erythropoiesis | Number of participants requiring dose reduction or dose discontinuation due to excessive erythropoiesis is reported. | Weeks 5 and 9 | 
| Change From Baseline in Ferritin at Week 13 | Baseline was defined as the average of the last 2 values prior to the first dose administration. | Baseline, Week 13 | 
| Change From Baseline in Transferrin Saturation (TSAT) at Week 13 |  | Baseline, Week 13 | 
| Change From Baseline in Reticulocyte Hemoglobin Content at Week 13 |  | Baseline, Week 13 | 
| Number of Participants With Mean Hb Values 11.0-13.0 g/dL at Weeks 6-9 and 10-13 |  | Weeks 6-9 and 10-13 | 
| Number of Participants With Mean Hb Values Within 11.0-13.0 g/dL During Weeks 10-13 Among Those With Maximum Hb ≥11.0 g/dL and Change of Hb ≥1 g/dL |  | Weeks 10-13 | 
| Number of Participants With Mean Hb Values Within 10.0-13.0 g/dL During Weeks 10-13 Among Those With Maximum Hb ≥10.0 g/dL and Change of Hb ≥1 g/dL |  | Weeks 10-13 | 
| Number of Participants With Mean Hb Values in Excess of 13.0 and 14.0 g/dL at Weeks 6-9 and 10-13 |  | Weeks 6-9 and 10-13 | 
| Number of Participants With Mean Hb Values <10.0 g/dL at Weeks 6-9 and 10-13 |  | Weeks 6-9 and 10-13 | 
| Number of Participants Requiring Rescue Treatment With an Erythropoiesis-Stimulating Agent (ESA), Red Blood Cells (RBC) Transfusion, or IV Iron (Excluding Arm C) | Number of participants requiring rescue treatment with an ESA, RBC transfusion, or IV Iron (Excluding Arm C) was reported. | Baseline up to Week 13 | 
| Number of Participants Requiring Therapeutic Phlebotomy | Number of participants who required therapeutic phlebotomy due to TEAE of abnormal erythropoiesis is reported. | Baseline up to Week 13 | 
| Number of Participants Withdrawn From the Study Due to Inadequate Efficacy | Number of participants withdrawn from the study due to inadequate efficacy is reported. | Baseline up to Week 16 | 
| Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 9 and 13 | The SF-36 V2 consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health perceptions, mental health, social function, and vitality. The physical functioning subscore and vitality subscore are reported. The scores ranged from 0 (worst) to 100 (Best). Higher score indicated a better health state. Baseline is defined as the last non-missing value prior to the first dose administration. | Baseline, Weeks 9 and 13 | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Anemia (FACT-An) Total Score at Weeks 9 and 13 | FACT-An is composed of 27 core items which assess participant's function in 4 domains and 20 anemia-related items, grouped into 5 subscales as follows: Physical well-being (PWB): 7 items; Social/family well-being (SWB): 7 items; Emotional well-being (EWB): 6 items; Functional well-being (FWB): 7 items; and Anemia: 20 items. All FACT-An items were rated as: 0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much. Each subscale score was the sum of scores for the items in the subscale. The FACT-An total score was the sum of all 5 subscale scores, ranging from 0 (worst) - 188 (best). Higher scores represented better quality of life. Baseline is defined as the last non-missing value prior to the first dose administration. | Baseline, Weeks 9 and 13 | 
| Number of Participants With Potentially Clinically Significant Laboratory Tests | Criteria for the potential clinical significance included: bilirubin (µmol/L) >1.5 * upper limit of normal (ULN), potassium (mmol/L) >1.2 * ULN, neutrophils (*10^9/L) ≤1, protein (g/L) >1.1 * ULN, leukocytes (*10^9/L) ≤2.5 or ≥15. | Baseline up to Week 16 | 
| Number of Participants With TEAEs | An adverse event (AE) was any untoward medical event in a participant who received study drug whether or not the event is considered drug related. TEAEs were defined as any event that either began or worsened after the first administration of study drug and within 28 days of the last dose. A summary of other nonserious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HD, Kidney, ESRD, Renal, End-Stage Renal Disease, Anemia, Oral anemia treatment, Hemoglobin levels, Hemodialysis, Peritoneal, PD, Hb, Erythropoietin, Blood count