Study of Roxadustat (FG-4592) in Participants With End-Stage Renal Disease Receiving Maintenance Hemodialysis

NCT ID: NCT01147666

Last Updated: 2022-01-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 161 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-17
• Study Completion Date: 2012-10-15

Brief Summary

The primary objective of this study is to evaluate the efficacy and safety of roxadustat in participants with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) therapy, previously treated with intravenous (IV) epoetin alfa.

Detailed Description

Dose ranging study with consecutive cohorts in two participant populations: participants normally responding to current anemia treatment (epoetin alfa) ("normoresponders": participants with baseline epoetin alfa dose at study entry 75 to 450 international units [IU]/kilograms [kg]/week) and participants not responding well to current treatment ("hyporesponders": participants with maintenance epoetin alfa dose above 450 IU/kg/week). Normoresponders are randomized to study drug roxadustat or epoetin alfa at a ratio of 3:1; hyporesponders are randomized to study drug roxadustat or epoetin alfa or placebo at a ratio of 2:1:1. The study objectives are to demonstrate that roxadustat is effective in maintaining hemoglobin (Hb) levels when converting from epoetin alfa and to establish optimum starting doses and dose adjustment regimens for Hb maintenance.

Conditions

End Stage Renal Disease; Anemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Cohort B (Epoetin Alfa)

Hyporesponsive participants will receive IV epoetin alfa treatments on Day 1, at their prestudy dose and according to their prestudy dosing schedule (TIW). Epoetin alfa dosing will occur on dialysis days in each Cohort B. Dose adjustment will be per local standard of care (exclusive of IV iron) for routine maintenance of stable Hb levels on dialysis participants.

Group Type: ACTIVE_COMPARATOR

Epoetin Alfa

Intervention Type: DRUG

Epoetin Alfa will be administered per dose and schedule specified in the arms.

Cohort B (Placebo)

Hyporesponsive participants will receive placebo matched to roxadustat, administered orally TIW for 19 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo matching to roxadustat will be administered per schedule specified in the arm.

Cohort A-1 (Roxadustat 1.0 mg/kg TIW)

Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.0 milligrams (mg)/kg, administered orally 3 times weekly (TIW) in the morning of the day after dialysis (interdialytic days) for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 grams \[g\]/deciliter \[dL\]) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-2 (Roxadustat 1.5 mg/kg TIW)

Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.5 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-3 (Roxadustat 2.0 mg/kg TIW)

Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-4 (Roxadustat 1.8 mg/kg TIW)

Normoresponsive participants (with baseline epoetin alfa dosage 25-85 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.8 mg/kg, administered orally TIW for 6 weeks. Participants who have not completed 6-week treatment at the time of Amendment 2, will continue treatment for up to 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-5 (Roxadustat 1.8 mg/kg TIW)

Normoresponsive participants (with baseline epoetin alfa dosage 85-115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.8 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-6 (Roxadustat 1.3 mg/kg TIW)

Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.3 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-7 (Weight Tiered Roxadustat 70-100-150 mg)

Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.3 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (\>60 to 90 kg), and heavy weight (\>90 to 140 kg) participants will receive roxadustat 70 mg, 100 mg, and 150 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-8 (Weight Tiered Roxadustat 70-120-200 mg)

Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.5 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (\>60 to 90 kg), and heavy weight (\>90 to 140 kg) participants will receive roxadustat 70 mg, 120 mg, and 200 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-9 (Roxadustat 2.0 mg/kg)

Normoresponsive participants (with baseline epoetin alfa dosage 85-150 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort A-10 (Weight Tiered Roxadustat 70-120-200 mg)

Normoresponsive participants (with baseline epoetin alfa dosage 25-115 IU/kg/dose at study entry) will receive tiered, weight-based initial doses of roxadustat (approximately 1.5 mg/kg/dose TIW). Low weight (40 to 60 kg), medium weight (\>60 to 90 kg), and heavy weight (\>90 to 140 kg) participants will receive roxadustat 70 mg, 120 mg, and 200 mg, respectively, administered as oral capsules for 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohorts A (Epoetin Alfa)

Normoresponsive participants will receive IV epoetin alfa treatments on Day 1, at their prestudy dose and according to their prestudy dosing schedule (TIW). Epoetin alfa dosing will occur on dialysis days in each Cohort A. Dose adjustment will be per local standard of care (exclusive of IV iron) for routine maintenance of stable Hb levels on dialysis participants.

Group Type: ACTIVE_COMPARATOR

Epoetin Alfa

Intervention Type: DRUG

Epoetin Alfa will be administered per dose and schedule specified in the arms.

Cohort B-1 (Roxadustat 1.5 mg/kg TIW)

Hyporesponsive participants (with baseline epoetin alfa dosage 125-400 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 1.5 mg/kg, administered orally TIW for 6 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Cohort B-2 (Roxadustat 2.0 mg/kg TIW)

Hyporesponsive participants (with baseline epoetin alfa dosage \>115 IU/kg/dose at study entry) will receive roxadustat capsules at a dose of 2.0 mg/kg, administered orally TIW for 6 weeks. Participants who have not completed 6-week treatment at the time of Amendment 2, will continue treatment for up to 19 weeks. Dose adjustment to achieve correction and subsequent maintenance of target Hb values (11.0-13.0 g/dL) will be based upon regular monitoring of Hb.

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

Roxadustat will be administered per dose and schedule specified in the arms.

Interventions

Roxadustat

Roxadustat will be administered per dose and schedule specified in the arms.

Intervention Type: DRUG

Epoetin Alfa

Epoetin Alfa will be administered per dose and schedule specified in the arms.

Intervention Type: DRUG

Placebo

Placebo matching to roxadustat will be administered per schedule specified in the arm.

Intervention Type: OTHER

Other Intervention Names

FG-4592

Eligibility Criteria

Inclusion Criteria

• ESRD and receiving maintenance HD TIW for ≥4 months prior to Day 1
• Two most recent Hb values obtained during screening period must be within the ranges set below:

i) Group A. Normoresponder Criteria: Hb range in the 8 weeks prior to randomization within 9.0 to 13.5 g/dL ii) Group B. Hyporesponder Criteria: Hb range in the 8 weeks prior to randomization within 8.5 to 13.5 g/dL

• Epoetin alfa, dose requirements:

i) Group A. Normoresponder Criteria - Cohorts A-1 to A-12: Stable IV epoetin alfa dose at baseline (that is, no more than a 30% fluctuation in the weekly dose) during the 4 weeks prior to study Day -3

1. Cohorts A-1 to A-4: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 85 IU/kg/dose, TIW; weekly dose between 75 and 255 IU/kg/week

2. Cohort A-5: Current and previous (past 4 weeks) epoetin alfa dose range ≥85 to 115 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week

3. Cohort A-9: Current and previous (past 4 weeks) epoetin alfa dose range ≥85 to 150 IU/kg/dose, TIW; total weekly dose between 255 and 450 IU/kg/week

4. Cohorts A-6 to A-8: Current and previous (past 4 weeks) epoetin alfa dose range 25 to 115 IU/kg/dose, TIW, and two times a week (BIW); total weekly dose between 75 and 345 IU/kg/week

5. Cohorts A-10 to A-12: Optional cohorts to be decided (TBD), dosing frequency and dose range to be determined by sponsor ii) Group B. Hyporesponder Criteria:

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1. Cohort B-1 (completed): Current and previous (past 4 weeks) epoetin alfa dose range 125 to 400 IU/kg/dose, TIW; weekly dose between 375 and 1200 IU/kg/week

2. Cohort B-2 to B-4: Current and previous (past 4 weeks) epoetin alfa dose range >115 IU/kg/dose, TIW; total weekly dose >345 IU/kg/week no requirement for stability of epoetin alfa doses

• Complete Blood Count (CBC), Hematology, liver function blood tests, serum folate and vitamin B12 within acceptable limits
• Absence of active or chronic gastrointestinal bleeding
• High sensitivity C-reactive protein (hsCRP) <60 mg/liter for normoresponders Cohorts A-8 through A-12 enrolled under Amendment 3; no hsCRP criteria for hyporesponders
• Body weight: 40 to 140 kg (dry weight)
• Body mass index (BMI): 18 to 45 kg/meter square (m^2)
• Dialysis vascular access via native arteriovenous fistula or synthetic graft, or permanent (tunneled) catheter (not via temporary catheter); permanent and temporary catheters, however, are still prohibited in Cohort A-5

Exclusion Criteria

• Anticipated change in HD prescription
• Any clinically significant infection or evidence of an underlying infection
• 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
• New York Heart Association Class III or IV congestive heart failure
• 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 myelodysplastic syndrome
• History of hemosiderosis, hemochromatosis, polycystic kidney disease, or anephric
• Active hemolysis or diagnosis of hemolytic syndrome
• Known bone marrow fibrosis
• Uncontrolled or symptomatic secondary hyperparathyroidism
• Any prior organ transplantation
• Drug-treated gastroparesis or short-bowel syndrome
• History of alcohol or drug abuse; or a positive drug screen for a substance that has not been prescribed for the participant
• Prior treatment with roxadustat
• Diagnosis or suspicion of renal cell carcinoma
• Red blood cell (RBC) transfusion within 12 weeks prior to Day 1, or anticipated need for RBC transfusion during the dosing period
• IV iron supplement within 2 weeks prior to Day 1 and/or unwilling to withhold IV iron during the dosing/treatment period

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Astellas Pharma Inc

INDUSTRY

Sponsor Role: collaborator

FibroGen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marietta Franco

Role: STUDY_DIRECTOR

FibroGen

Locations

Tempe, Arizona, United States

Pine Bluff, Arkansas, United States

Azusa, California, United States

Los Angeles, California, United States

Northridge, California, United States

Ontario, California, United States

Paramount, California, United States

Yuba City, California, United States

Miami, Florida, United States

Pembroke Pines, Florida, United States

Honolulu, Hawaii, United States

Louisville, Kentucky, United States

Detroit, Michigan, United States

Kansas City, Missouri, United States

Paterson, New Jersey, United States

New York, New York, United States

Rosedale, New York, United States

Williamsville, New York, United States

Toledo, Ohio, United States

Orangeburg, South Carolina, United States

Arlington, Texas, United States

Fort Worth, Texas, United States

Houston, Texas, United States

San Antonio, Texas, United States

Fairfax, Virginia, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 36005278 (View on PubMed)

Other Identifiers

FGCL-4592-040

Identifier Type: -

Identifier Source: org_study_id