A Study of Roxadustat for the Treatment of Anemia in Participants With Chronic Kidney Disease and Not Receiving Dialysis

A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat (FG-4592) for the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

The purpose of this study is to determine whether roxadustat is safe and effective in the treatment of anemia in participants with chronic kidney disease and not on dialysis.

Study Overview

• Status: Completed
• Conditions: CKD Anemia
• Intervention / Treatment: Drug: Placebo; Drug: Roxadustat

Detailed Description

There is a screening period of up to 6 weeks, a variable treatment period for individual participants. In order to complete the treatment period simultaneously for all study participants, the minimum treatment duration may be less than 52 weeks, with a maximum treatment duration of up to 3 years after the last participant is randomized, and a post-treatment follow-up period of 4 weeks. Participants who prematurely discontinued from treatment will be expected to complete the Early Termination (ET) and End of Study (EOS) visits. Such participants will be considered non-completers, but they will be expected to participate in long-term follow-up (LTFU) for cardiovascular events (CV) of interest, vital status, and hospitalizations until overall study closure unless the participant withdrew consent for this LTFU data collection. Participants were randomized in a 2:1 ratio to receive either roxadustat or placebo in a double-blind manner.

• Study Type: Interventional
• Enrollment (Actual): 922
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1852FZD
    • Investigational Site
  • Buenos Aires, Argentina, C1425BPJ
    • Investigational Site
  • Buenos Aires, Argentina, C1429BWN
    • Investigational Site
  • Cordoba, Argentina, 5000
    • Investigational Site
  • Cordoba, Argentina, X5002AOQ
    • Investigational Site
  • Cordoba, Argentina, X5016KET
    • Investigational Site
  • Corrientes, Argentina, 3400
    • Investigational Site
  • Mendoza, Argentina, 5500
    • Investigational Site
  • Salta, Argentina, A4402BGJ
    • Investigational Site
  • Santa Fe, Argentina, 3000
    • Investigational Site
  • Buenos Aires
    • Ciudad Evita, Buenos Aires, Argentina, B1178IFA
      • Investigational Site
    • Moron, Buenos Aires, Argentina, B1708DPN
      • Investigational Site
  • Provincia De Buenos Aires
    • González Catán, Provincia De Buenos Aires, Argentina, B1759LTF
      • Investigational Site
    • Junin, Provincia De Buenos Aires, Argentina, B6000GMA
      • Investigational Site
    • Pergamino, Provincia De Buenos Aires, Argentina, B2700CPM
      • Investigational Site
    • Villa Domínico, Provincia De Buenos Aires, Argentina, B1874GBA
      • Investigational Product
  • Provincia De Cordoba
    • Ciudad de Cordoba, Provincia De Cordoba, Argentina, X5002HWE
      • Investigational Site
• Australia
  • Gosford, Australia, 2250
    • Investigational Site
  • Hobart, Australia, 7000
    • Investigational Site
  • Launceston, Australia, 7250
    • Investigational Site
  • Melbourne, Australia, 3004
    • Investigational Site
  • New Lambton Heights, Australia, 2305
    • Investigational Site
  • Randwick, Australia, 2031
    • Investigational Site
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Investigational Site
• Chile
  • Region De La Araucania
    • Temuco, Region De La Araucania, Chile, 4781151
      • Investigational Site
  • Region Metropolitana
    • Santiago, Region Metropolitana, Chile, 8431657
      • Investigational Site
• Colombia
  • Atlantico
    • Barranquilla, Atlantico, Colombia
      • Investigational Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia
      • Investigational Site
• Hong Kong
  • Chai Wan, Hong Kong
    • Investigational Site
  • Shatin, Hong Kong, 852
    • Investigational Site
  • Tai Po, Hong Kong
    • Investigational Site
  • Pokfulam
    • Hong Kong, Pokfulam, Hong Kong
      • Investigational Site
• Korea, Republic of
  • Busan, Korea, Republic of, 614-735
    • Investigational Site
  • Seoul, Korea, Republic of, 130-872
    • Investigational Site
  • Seoul, Korea, Republic of, 134-727
    • Investigational Site
  • Seoul, Korea, Republic of, 110-744
    • Investigational Site
  • Seoul, Korea, Republic of, 133-791
    • Investigational Site
  • Seoul, Korea, Republic of, 137-701
    • Investigational Site
  • Seoul, Korea, Republic of, 143-729
    • Investigational Site
  • Seoul, Korea, Republic of
    • Investigational Site
  • Gyeonggi-Do
    • Anyang-Si, Gyeonggi-Do, Korea, Republic of, 431-796
      • Investigational Site
    • Goyang-Si, Gyeonggi-Do, Korea, Republic of, 410-719
      • Investigational Site
    • Guri-Si, Gyeonggi-Do, Korea, Republic of, 471-701
      • Investigational Site
    • Seongnam-Si, Gyeonggi-Do, Korea, Republic of, 463-712
      • Investigational Site
• Malaysia
  • Alor Setar, Malaysia, 05460
    • Investigational Site
  • Kajang, Malaysia, 43000
    • Investigational Site
  • Kuala Lumpur, Malaysia, 50586
    • Investigational Site
  • Kuala Lumpur, Malaysia, 59100
    • Investigational Site
  • Kuching, Malaysia, 93586
    • Investigational Site
  • Pulau Pinang, Malaysia, 10990
    • Investigational Site
  • Sungai Petani, Malaysia, 080000
    • Investigational Site
  • Taiping, Malaysia, 34000
    • Investigational Site
• Mexico
  • Aguascalientes, Mexico, 20128
    • Investigational Site
  • San Luis Potosi, Mexico, 78240
    • Investigational Site
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 06100
      • Investigational Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Investigational Site
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64000
      • Investigational Site
  • Yucatan
    • Merida, Yucatan, Mexico, 97133
      • Investigational Site
• New Zealand
  • Auckland, New Zealand
    • Investigational Site
  • Hamilton, New Zealand, 3240
    • Investigational Site
  • Tauranga, New Zealand, 3143
    • Investigational Site
• Peru
  • Lima, Peru, Lima 13
    • Investigational Site
  • Lima, Peru, Lima 1
    • Investigational Site
  • Callao
    • Bellavista, Callao, Peru, Callao 2
      • Investigational Site
  • Lima
    • San Martin de Porres, Lima, Peru, Lima 31
      • Investigational Site
• Philippines
  • Pasig, Philippines
    • Investigational Site
  • Quezon City, Philippines, 1100
    • Investigational Site
  • Quezon City, Philippines, 1102
    • Investigational Site
  • Cavite
    • Dasmarinas, Cavite, Philippines, 4114
      • Investigational Site
  • Davao
    • Davao City, Davao, Philippines, 8000
      • Investigational Site
• Puerto Rico
  • Ponce, Puerto Rico, 00716
    • Investigational Site
  • San Juan, Puerto Rico, 00918
    • Investigational Site
• Singapore
  • Singapore, Singapore, 119074
    • Investigational Site
  • Singapore, Singapore, 768828
    • Investigational Site
  • Singapore, Singapore
    • Investigational Site
• Taiwan
  • Changhua, Taiwan, 500
    • Investigational Site
  • Hualien City, Taiwan, 970
    • Investigational Site
  • Kaohsiung, Taiwan, 83301
    • Investigational Site
  • Kaohsiung, Taiwan, 40705
    • Investigational Site
  • Kaohsiung, Taiwan, 81362
    • Investigational Site
  • Taichung, Taiwan, 433
    • Investigational Site
  • Taichung, Taiwan, 40705
    • Investigational Site
  • Tainan, Taiwan, 704
    • Investigational Site
  • Tainan City, Taiwan, 433
    • Investigational Site
  • Taipei, Taiwan, 10002
    • Investigational Site
  • Taipei, Taiwan, 110
    • Investigational Site
  • Taipei, Taiwan, 11490
    • Investigational Site
• Thailand
  • Bangkok, Thailand, 10400
    • Investigational Site
  • Bangkok, Thailand, 10330
    • Investigational Site
  • Chiang Mai, Thailand, 50200
    • Investigational Site
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Investigational Site
  • Arizona
    • Tempe, Arizona, United States, 85284
      • Investigational Site
  • California
    • Alhambra, California, United States, 91801
      • Investigational Site
    • Chula Vista, California, United States, 91910
      • Investigational Site
    • Inglewood, California, United States, 90301
      • Investigational Site
    • La Mesa, California, United States, 91942
      • Investigational Site
    • La Palma, California, United States, 91324
      • Investigational Site
    • Lynwood, California, United States, 90262
      • Investigational Site
    • Northridge, California, United States, 91325
      • Investigational Site
    • Paramount, California, United States, 90723
      • Investigational Site
    • Riverside, California, United States, 92503
      • Investigational Site
    • Roseville, California, United States, 95661
      • Investigational Site
    • San Dimas, California, United States, 91773
      • Investigational Site
    • Whittier, California, United States, 90603
      • Investigational Site
  • Florida
    • Coral Gables, Florida, United States, 33134
      • Investigational Site
    • Cutler Bay, Florida, United States, 33157
      • Investigational Site
    • Hialeah, Florida, United States, 33016
      • Investigational Site
    • Miami, Florida, United States, 33135
      • Investigational Site
    • Miami, Florida, United States, 33015
      • Investigational Site
    • Miami, Florida, United States, 33122
      • Investigational Site
    • Miami, Florida, United States, 33150
      • Investigational Site
    • Ocala, Florida, United States, 34471
      • Investigational Site
    • Pembroke Pines, Florida, United States, 33028
      • Investigational Site
    • South Miami, Florida, United States, 33143
      • Investigational Site
    • Winter Park, Florida, United States, 32789
      • Investigational Site
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Investigational Site
  • Idaho
    • Caldwell, Idaho, United States, 83605
      • Investigational Site
  • Louisiana
    • Shreveport, Louisiana, United States, 71101
      • Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Investigational Site
    • Flint, Michigan, United States, 48503
      • Investigational Site
    • Flint, Michigan, United States, 48532
      • Investigational Site
    • Pontiac, Michigan, United States, 48341
      • Investigational Site
    • Roseville, Michigan, United States, 48066
      • Investigational Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Investigational Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Investigational Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Investigational Site
  • New York
    • Bronx, New York, United States, 10461
      • Investigational Site
    • Mineola, New York, United States, 11501
      • Investigational Site
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Investigational Site
    • Raleigh, North Carolina, United States, 27609
      • Investigational Site
    • Rocky Mount, North Carolina, United States, 27804
      • Investigational Site
    • Winston-Salem, North Carolina, United States, 27103
      • Investigational Site
  • Pennsylvania
    • Beaver, Pennsylvania, United States, 15009
      • Investigational Site
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • Investigational Site
    • Sumter, South Carolina, United States, 29150
      • Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Investigational Site
  • Texas
    • Arlington, Texas, United States, 76015
      • Investigational Site
    • Corsicana, Texas, United States, 75110
      • Investigational Site
    • Dallas, Texas, United States, 75246
      • Investigational Site
    • Houston, Texas, United States, 77030
      • Investigational Site
    • San Antonio, Texas, United States, 78229
      • Investigational Site
  • Virginia
    • Fairfax, Virginia, United States, 22033
      • Investigational Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic kidney disease Stages 3, 4, or 5 and not receiving dialysis
• Anemia qualified by measurements of hemoglobin values during screening
• Additional blood work must be in a safe range for study entry
• Body weight 45 to 160 kilograms (kg)
• Willingness to use contraception if of child-bearing potential

Exclusion Criteria:

• Treatment with an erythropoiesis-stimulating agent (ESA) within 12 weeks prior to study participation
• More than 1 dose of intravenous iron within 12 weeks prior to study participation
• Blood transfusion within 8 weeks prior to study participation
• Active infection
• Chronic liver disease
• Severe congestive heart failure, recent heart attack, stroke, seizure, or blood clot
• Uncontrolled blood pressure within 2 weeks prior to study participation
• Renal cell carcinoma
• History of malignancy, including multiple myeloma or other myelodysplastic syndrome
• Chronic inflammatory disease that could impact red blood cell production
• Any prior organ transplant or a scheduled organ transplantation
• Anticipated elective surgery that is expected to lead to significant blood loss or anticipated elective heart procedure
• Gastrointestinal bleeding
• Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)
• Recent use of an investigational drug or treatment, or participation in an investigational study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Roxadustat; Participants will receive roxadustat tablets orally 3 times a week (TIW). The initial dose will be according to the tiered weight-based approach, with starting roxadustat doses of 70 milligrams (mg) TIW to participants weighing <70 kilograms (kg) and roxadustat doses of 100 mg TIW to participants weighing ≥70 kg. Dose-titration (up to a maximum dose of 300 mg) will be performed based upon regular measurement of Hb levels until the participant achieves central Hb value of ≥11.0 grams/deciliter (g/dL) and Hb increase from baseline (BL) of ≥1.0 g/dL at 2 consecutive study visits, separated by at least 5 days. Once target Hb level is reached, the participant will enter the maintenance period during which roxadustat dosage will be adjusted every 4 weeks to maintain participant's Hb level within the target range of 10.0 g/dL and 12.0 g/dL. The maximum treatment duration will be up to 234.9 weeks.	Drug: Roxadustat; Oral tablets; Other Names: FG-4592; ASP1517; AZD9941
Placebo Comparator: Placebo; Participants will receive roxadustat-matching placebo tablets orally TIW. The initial dose will be according to the tiered weight-based approach, with starting roxadustat-matching placebo doses of 70 mg TIW to participants weighing <70 kg and roxadustat-matching placebo doses of 100 mg TIW to participants weighing ≥70 kg. Dose-titration (up to a maximum dose of 300 mg) will be performed based upon regular measurement of Hb levels until the participant achieves central Hb value of ≥11.0 g/dL and Hb increase from BL of ≥1.0 g/dL at 2 consecutive study visits, separated by at least 5 days. Once target Hb level is reached, the participant will enter the maintenance period during which roxadustat dosage will be adjusted every 4 weeks to maintain participant's Hb level within the target range of 10.0 g/dL and 12.0 g/dL. The maximum treatment duration will be up to 208.1 weeks.	Drug: Placebo; Oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
United States (US FDA) Submission: Mean Change From Baseline in Hb (g/dL) Over Weeks 28 to 52 Regardless of Rescue Therapy	The change in Hb from baseline to the average level during the evaluation period (defined as Week 28 until Week 52) is reported. Hb values under the influence of a rescue therapy were not censored. The intermittent missing hemoglobin data were imputed for each treatment relying on non-missing data from all participants within each treatment group using the Monte Carlo Markov Chain (MCMC) imputation model, Monotone missing data were imputed by regression from its own treatment group. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study drug.	Baseline (Day 1, Week 0), Weeks 28 to 52
Ex-US Submission: Number (%) of Participants Who Achieved a Hb Response During the First 24-Weeks of Treatment Censoring for Rescue Therapy	The number of participants who achieved a Hb response at 2 consecutive visits at least 5 days apart during the first 24 weeks of treatment, without rescue therapy (that is, red blood cell [RBC] transfusion, erythropoiesis-stimulating agent [ESA], or intravenous [IV] iron) are reported. A Hb response is defined, using central laboratory values, as the following: Hb ≥11 g/dL and Hb increase from baseline by ≥1 g/dL in participants with baseline Hb >8 g/dL, or; An increase in Hb by ≥2 g/dL in participants with baseline Hb ≤8.0 g/dL	Baseline up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Hb Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy	For Ex-US submission only: Hb values under the influence of a rescue therapy were censored by mixed effect model of repeated measures (MMRM) for up to 6 weeks. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study drug.	Baseline (Day 1, Week 0), Weeks 28 to 36
Mean Change From Baseline in Hb Averaged Over Weeks 28 to 52 Regardless of Rescue Therapy in Participants With Baseline C-Reactive Protein (CRP) >Upper Limit of Normal (ULN)	Hb values under the influence of a rescue therapy were not censored in the analysis. The intermittent missing hemoglobin data were imputed for each treatment relying on non-missing data from all participants within each treatment group using the MCMC imputation model, Monotone missing data were imputed by regression from its own treatment group. Baseline Hb was defined as the mean of up to 4 last central laboratory values prior to the first dose of study treatment.	Baseline (Day 1, Week 0), Weeks 28 to 52
Number (%) of Participants With Hb ≥10 g/dL Averaged Over Weeks 28 to 36 With Censoring for Rescue Therapy	Hb values under the influence of a rescue therapy were censored by Cochran-Mantel-Haenszel Test for up to 6 weeks. Responder was defined as: Hb ≥10.0 g/dL, which was based on central laboratory values.	Weeks 28 to 36
Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 28	Baseline LDL cholesterol was defined as the last LDL cholesterol value prior to the first dose of study drug.	Baseline (Day 1, Week 0), Weeks 12 to 28
Rate of Change in eGFR From Baseline up to 12 Months (Linear Random Coefficient Model With Observed Data)	Progression of chronic kidney disease was measured by rate of change in eGFR over time adjusted by baseline eGFR, with censoring for chronic dialysis or kidney transplant, using random slope and intercept model. Least Square Mean of change from baseline at 1 year was derived based on a random slopes and intercepts model using all available eGFR values (1 baseline and all post-treatment values up to end of treatment period + 7 days or start of dialysis) adjusted on treatment, baseline Hb, baseline eGFR, geographical region, cardiovascular events history at Baseline (yes vs. no), time (continuous value), the interaction terms of baseline eGFR by time, baseline Hb by time, and treatment by time as fixed effects, with random effects of intercept and linear slope of time. All assessments collected after the start of stable dialysis or kidney transplant were excluded from the analysis.	Baseline, Month 12
Number of Participants Who Received Blood/RBC Transfusion in the First 52 Weeks of Treatment	Participants with any use of blood/RBC transfusion were reported.	Baseline up to Week 52
Number (%) of Participants Who Received Rescue Therapy in the First 24 Weeks and in the First 52 Weeks of Treatment	Rescue therapy included any use of RBC transfusion, ESA, or IV iron.	Baseline (Day 1, Week 0) up to Week 24 and up to Week 52
Change From Baseline in Short Form 36 (SF-36) Version 2 Physical Functioning Subscore and Vitality Subscore at Weeks 12 to 28	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). A higher score indicates a general improvement of life quality or well-being. Baseline score was defined as the last physical functioning value or vitality value, as applicable, prior to the first dose of study drug.	Baseline (Day 1, Week 0), Weeks 12 to 28
Number (%) of Participants Who Experienced Exacerbation of Hypertension	Exacerbation of hypertension was defined as an increase from baseline of ≥20 millimeter of mercury (mmHg) in systolic blood pressure (sBP) and sBP ≥170 mmHg or an increase from baseline of ≥15 mmHg in diastolic blood pressure (dBP) and dBP ≥110 mmHg.	Baseline up to Week 52
Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 20 to 28	Baseline MAP was defined as the last MAP value prior to the first dose of study drug.	Baseline, Weeks 20 to 28

Collaborators and Investigators

• Sponsor: FibroGen
• Collaborators: AstraZeneca; Astellas Pharma Europe B.V.
• Investigators: Study Chair: Mark Eisner, MD, MPH, FibroGen

Publications and helpful links

General Publications

• 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.
• Provenzano R, Szczech L, Leong R, Saikali KG, Zhong M, Lee TT, Little DJ, Houser MT, Frison L, Houghton J, Neff TB. Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials. Clin J Am Soc Nephrol. 2021 Aug;16(8):1190-1200. doi: 10.2215/CJN.16191020.
• Coyne DW, Roger SD, Shin SK, Kim SG, Cadena AA, Moustafa MA, Chan TM, Besarab A, Chou W, Bradley C, Eyassu M, Leong R, Lee TT, Saikali KG, Szczech L, Yu KP. Roxadustat for CKD-related Anemia in Non-dialysis Patients. Kidney Int Rep. 2020 Dec 5;6(3):624-635. doi: 10.1016/j.ekir.2020.11.034. eCollection 2021 Mar.

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2012
• Primary Completion (Actual): September 24, 2018
• Study Completion (Actual): September 24, 2018

Study Registration Dates

• First Submitted: December 11, 2012
• First Submitted That Met QC Criteria: December 14, 2012
• First Posted (Estimate): December 17, 2012

Study Record Updates

• Last Update Posted (Actual): October 1, 2021
• Last Update Submitted That Met QC Criteria: September 1, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: anemia; Hemoglobin (Hb); non-dialysis; ASP1517; End-Stage Renal Disease; AZD9941; chronic kidney disease (CKD); erythropoeitin; erythropoeisis stimulating-agent
• Additional Relevant MeSH Terms: Urologic Diseases; Hematologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Anemia
• Other Study ID Numbers: FGCL-4592-060

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No