Clinical trial NCT01147666: Study of Roxadustat (FG-4592) in Participants With End-Stage Renal Disease Receiving Maintenance Hemodialysis
Official title: A Phase 2, Randomized, Open-Label Active-Comparator (Epoetin Alfa) and Single-Blind Placebo-Controlled, Dose-Ranging Safety and Exploratory Efficacy Study of FG-4592 in Subjects With End-Stage Renal Disease Receiving Maintenance Hemodialysis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: End Stage Renal Disease
Anemia
Keywords: Kidney
End Stage Renal Disease
ESRD
Chronic Kidney Disease
CKD
Renal
Anemia
Oral anemia treatment
Hemoglobin levels
Blood count
Erythropoietin
Hemodialysis
Normoresponder
Hyporesponder
Lead sponsor: FibroGen
Sponsor class: INDUSTRY
Collaborators: name: AstraZeneca
name: Astellas Pharma Inc
First posted: 2010-06-22
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Key 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

Key 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

Primary outcomes:
measure: Number of Participants With Week 7 Hb ≥ Baseline Hb - 0.5 g/dL, Among Normoresponder Participants Treated for 6 Weeks Only
timeFrame: Week 7
measure: Number of Participants With Week 7 Hb ≥ Baseline Hb - 0.5 g/dL, Among Hyporesponsive Participants Treated for at Least 6 Weeks
timeFrame: Week 7
measure: Number of Participants With a Mean Hb Above 11 g/dL When the Mean Hb Values at Weeks 17, 18, 19, and 20 Were Averaged, Among Participants Treated for 19 Weeks
timeFrame: Weeks 17, 18, 19, and 20
Secondary outcomes:
measure: Number of Participants With a Mean of Hb Within 11-13 g/dL (Values Obtained at Weeks 17, 18, 19, and 20 for Participants Dosed for 19 Weeks)
timeFrame: Weeks 17, 18, 19, and 20
measure: Number of Participants With a Mean of Hb Within 10-13 g/dL (Values Obtained at Weeks 17, 18, 19, and 20 for Participants Dosed for 19 Weeks)
timeFrame: Weeks 17, 18, 19, and 20
measure: Change From Baseline in Hb at Week 7 for Participants Treated for at Least 6 Weeks
timeFrame: Baseline, Week 7
measure: Change From Baseline in Hb at Weeks 8, 10, 12, 14, 17, 19, and 20 for Participants Treated for 7-19 Weeks
timeFrame: Baseline, Weeks 8, 10, 12, 14, 17, 19, and 20
measure: Number of Participants Who Required Dose Adjustments During the Dosing Period for Participants Treated for 6 Weeks Only
timeFrame: Baseline up to Week 6
measure: Number of Participants Who Required Dose Adjustments During the Dosing Period for Participants Treated for 19 Weeks
timeFrame: Baseline up to Week 19
measure: Number of Participants Whose Hb Levels Were Maintained at Week 7 to Within ±1 g/dL of Their Mean 4-Week Screening Period Baseline Value for Participants Treated for At Least 6 Weeks
timeFrame: Week 7
measure: Number of Participants Whose Hb Levels Were Maintained at Week 7 to Within ±1 g/dL of Their Mean 4-Week Screening Period Baseline Value for Participants Treated for 19 Weeks
timeFrame: Week 7
measure: Number of Participants Treated for 6 Weeks Only Whose Hb Levels at Week 7 Were Greater Than Their Baseline Level
timeFrame: Week 7
measure: Number of Participants Treated for 7-19 Weeks Whose Hb Levels at Weeks 8, 10, 12, 14, 17, 19, and 20 Were Greater Than Their Baseline Level
timeFrame: Weeks 8, 10, 12, 14, 17, 19, and 20
measure: Number of Participants Who Required Rescue Anemia Treatment Due to Hb Levels, Among Participants Treated for at Least 6 Weeks
timeFrame: Baseline up to Week 6
measure: Number of Participants Who Required Rescue Anemia Treatment Due to Hb Levels, Among Participants Treated for 19-Weeks
timeFrame: Baseline up to Week 19
measure: Number of Participants Requiring Dose Reduction Secondary to Excessive Erythropoiesis During Dosing Period, Among Participants Treated for at Least 6-Weeks
timeFrame: Baseline up to Week 6
measure: Number of Participants Requiring Dose Reduction Secondary to Excessive Erythropoiesis During Dosing Period, Among Participants Treated for 19-Weeks
timeFrame: Baseline up to Week 19
measure: Rate of Change in Hb Levels, Measured by Regression Slopes of the Hb Values During Treatment up to Week 6
timeFrame: Baseline up to Week 6
measure: Trough Plasma Concentration of Roxadustat and Epoetin Alfa
timeFrame: Predose, 4, 8, 12, 24, 48, and 72 hours postdose at Weeks 1 and 6
Other outcomes:
Locations:
city: Tempe
country: United States
state: Arizona
city: Pine Bluff
country: United States
state: Arkansas
city: Azusa
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Northridge
country: United States
state: California
city: Ontario
country: United States
state: California
city: Paramount
country: United States
state: California
city: Yuba City
country: United States
state: California
city: Miami
country: United States
state: Florida
city: Pembroke Pines
country: United States
state: Florida
city: Honolulu
country: United States
state: Hawaii
city: Louisville
country: United States
state: Kentucky
city: Detroit
country: United States
state: Michigan
city: Kansas City
country: United States
state: Missouri
city: Paterson
country: United States
state: New Jersey
city: New York
country: United States
state: New York
city: Rosedale
country: United States
state: New York
city: Williamsville
country: United States
state: New York
city: Toledo
country: United States
state: Ohio
city: Orangeburg
country: United States
state: South Carolina
city: Arlington
country: United States
state: Texas
city: Fort Worth
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Fairfax
country: United States
state: Virginia
Study officials:
affiliation: FibroGen
name: Marietta Franco
role: STUDY_DIRECTOR
References:
citation: 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.