Safety and Efficacy Study of Roxadustat (FG-4592) for the Treatment of Anemia in End-Stage Renal Disease (ESRD) Newly Initiated Dialysis Participants

NCT ID: NCT02052310

Last Updated: 2021-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1043 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-11
• Study Completion Date: 2018-09-21

Brief Summary

The purpose of this study is to determine whether roxadustat is safe and effective in the treatment of anemia in participants who have just begun dialysis treatment for ESRD.

Detailed Description

There is a screening period of up to 6 weeks, a treatment period of a minimum of 52 weeks and a maximum of approximately up to 3 years after last participant is randomized, and a post-treatment follow-up period of 4 weeks. Participants will be randomized in a 1:1 ratio to receive either open-label roxadustat or epoetin alfa (active control).

Conditions

Anemia in Incident Dialysis Patients

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Roxadustat

Participants will receive roxadustat tablets, administered orally 3 times weekly (TIW). Initial roxadustat dose will be based on a tiered, weight-based dosing scheme (low weight \[≤70 kilograms (kg)\] and high weight \[\>70 to 160 kg\] participants will receive 70 and 100 milligrams \[mg\] roxadustat, respectively). Dose adjustment to achieve correction and subsequent maintenance of target hemoglobin (Hb) values (10-12 grams \[g\]/deciliter \[dL\]) will be based upon regular monitoring of Hb. The maximum roxadustat dose is 3.0 mg/kg per dose or 400 mg per administration (whichever is lower).

Group Type: EXPERIMENTAL

Roxadustat

Intervention Type: DRUG

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

Epoetin Alfa

Participants on hemodialysis (HD) will receive epoetin alfa, administered intravenously (IV) TIW, with starting doses and dose adjustment rules as per United States Package Insert (USPI) or summary of product characteristics (SmPC). Participants on home HD or peritoneal dialysis (PD) will receive epoetin alfa, administered subcutaneously (SC) as per the country-specific product label (USPI or SmPC) or local standard of care (SOC).

Group Type: ACTIVE_COMPARATOR

Epoetin Alfa

Intervention Type: DRUG

Epoetin alfa will be administered TIW according to the epoetin alfa USPI or SmPC, or local SOC.

Interventions

Roxadustat

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

Intervention Type: DRUG

Epoetin Alfa

Epoetin alfa will be administered TIW according to the epoetin alfa USPI or SmPC, or local SOC.

Intervention Type: DRUG

Other Intervention Names

ASP1517; AZD9941; FG-4592; Procrit; Epogen

Eligibility Criteria

Inclusion Criteria

• Participant has been informed of the investigational nature of this study and has given written informed consent in accordance with institutional, local, and national guidelines.
• Receiving HD or PD for ESRD for a minimum of 2 weeks and a maximum of 4 months, prior to randomization.
• Hemodialysis access consisting of an arteriovenous (AV) fistula, AV graft, or tunnelled (permanent) catheter; or PD catheter in use.
• Mean of the two most recent predialysis Hb values during the Screening Period, obtained at least 2 days apart, must be ≤ 10.0 g/dL, with a difference of ≤ 1.3 g/dL between the highest and the lowest values. The last Hb value must be drawn within 10 days prior to randomization.
• Ferritin ≥ 100 nanograms (ng)/milliliter (mL) (≥ 220 picomoles (pmol)/L); participants with ferritin level < 100 ng/mL(<220 pmol/L) during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest ferritin prior to randomization.
• Transferrin saturation ≥ 20%; participants with TSAT level < 20% during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest TSAT prior to randomization.
• Serum folate level, performed within 8 weeks prior to randomization ≥ lower limit of normal (LLN); participants with serum folate level < LLN during screening, qualify after receiving folate supplement (per local standard of care), without the need to retest folate prior to randomization.
• Serum vitamin B12 level, performed within 8 weeks prior to randomization ≥ LLN; participants with vitamin B12 level < LLN during screening, qualify after receiving B12 supplement (per local standard of care), without the need to retest B12 prior to randomization.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 * upper limit of normal (ULN), and total bilirubin ≤ 1.5 * ULN.
• Body weight up to 160 kg (HD participants: dry weight).

Exclusion Criteria

• Total duration of prior effective ESA use must be ≤3 weeks within the preceding 12 weeks at the time informed consent is obtained.

Specific dosing guidance, depending on the type of ESAs, injected IV or SC within 12 weeks prior to start of screening are as follows:

i) Short-acting ESAs (EPO-alfa or equivalents) - IV: Up to 9 doses, last EPO dose must be ≥2 days prior to start of screening; SC: Up to 3 doses, last EPO dose must be ≥1 week (7 days) prior to start of screening ii) Darbepoetin - IV: Up to 3 doses, last darbepoetin dose must be ≥1 week (7 days) prior to start of screening; SC: Up to 2 doses, last darbepoetin dose must be ≥2 weeks (14 days) prior to start of screening iii) Continuous erythropoietin receptor activator (CERA) IV and SC: Up to 2 doses; last CERA dose must be ≥2 weeks (14 days) prior to start of screening

• Intravenous iron: there is no restriction regarding IV iron use during screening, provided it is administered in accordance with local SOC.
• Red blood cell transfusion within 4 weeks prior to randomization.
• Active, clinically significant infection that could be manifested by white blood cell (WBC) count > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection at the time of randomization.
• History of chronic liver disease (for example, chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis, or fibrosis of the liver).
• New York Heart Association Class III or IV congestive heart failure at screening.
• Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event within a major vessel (excluding vascular dialysis access) (for example, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
• Uncontrolled hypertension, in the opinion of the Investigator, (for example, that requires a change in anti-hypertensive medication) within 2 weeks prior to randomization.
• Renal imaging performed within 12 weeks prior to randomization indicative of a diagnosis or suspicion (for example, complex kidney cyst of Bosniak Category 2 or higher) of renal cell carcinoma.
• History of malignancy, except for 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.
• Positive for any of the following: human immunodeficiency virus (HIV); hepatitis B surface antigen (HBsAg); or anti-hepatitis C virus antibody (anti-HCV Ab).
• Chronic inflammatory disease that could impact erythropoiesis (for example, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
• Known, untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration, or retinal vein occlusion (participants who are already blind for the above reasons qualify to participate).
• Known history of myelodysplastic syndrome or multiple myeloma.
• Known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than chronic kidney disease (CKD).
• Known hemosiderosis, hemochromatosis, coagulation disorder, or a hypercoagulable condition.
• Organ transplant: participants with any of the following:

1. Experienced rejection of a transplanted organ within 6 months of transplantation

2. Currently on high doses of immunosuppressive therapy (per discretion of the Investigator)

3. Scheduled for organ transplantation. Note: being on a waiting list for kidney transplant is not exclusionary

• Anticipated elective surgery, except for vascular access surgery or dialysis catheter placement, that is expected to lead to significant blood loss, or anticipated elective coronary revascularization.
• Active or chronic gastrointestinal bleeding.
• Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
• Use of iron-chelating agents within 4 weeks prior to randomization.
• Known hypersensitivity reaction to any ESA.
• Use of an investigational drug or treatment, participation in an investigational study, or presence of an expected carryover effect of an investigational treatment, within 4 weeks prior to randomization.
• Anticipated use of dapsone or androgens at any dose amount or chronic use of acetaminophen or paracetamol > 2.0 g/day during the study.
• History of alcohol or drug abuse within 6 months prior to randomization.
• Females of childbearing potential, unless using contraception as detailed in the protocol; male participants with sexual partners of childbearing potential who are not on birth control unless the male participant agrees to use contraception.
• Pregnant or breastfeeding females.
• Any medical condition that, in the opinion of the Investigator, may pose a safety risk to a participant in this study, may confound efficacy or safety assessment, or may interfere with study participation.

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

Sponsors

Astellas Pharma Europe B.V.

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

FibroGen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Charles Bradley, PhD

Role: STUDY_DIRECTOR

FibroGen

Locations

Investigational Site

Chula Vista, California, United States

Investigational Site

La Mesa, California, United States

Investigational Site

San Diego, California, United States

Investigational Site

Coral Springs, Florida, United States

Investigational Site

Lauderdale Lakes, Florida, United States

Investigational Site

Miami, Florida, United States

Investigational Site

Miami, Florida, United States

Investigational Site

Tampa, Florida, United States

Meridian

Meridian, Idaho, United States

Investigational Site

Shreveport, Louisiana, United States

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Detroit, Michigan, United States

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Pontiac, Michigan, United States

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Brookhaven, Mississippi, United States

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Columbus, Mississippi, United States

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Gulfport, Mississippi, United States

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Tupelo, Mississippi, United States

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Saint Ann, Missouri, United States

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St Louis, Missouri, United States

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Portsmouth, New Hampshire, United States

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Albuquerque, New Mexico, United States

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Durham, North Carolina, United States

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New Bern, North Carolina, United States

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Columbus, Ohio, United States

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Columbia, South Carolina, United States

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Orangeburg, South Carolina, United States

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Sumter, South Carolina, United States

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Knoxville, Tennessee, United States

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Edinburg, Texas, United States

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Houston, Texas, United States

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Houston, Texas, United States

Investigational Site

Serandi, Buenos Aires, Argentina

Investigational Site

Santa Fe, IX Region, Argentina

Investigational Site

Burgas, , Bulgaria

Investigational site

Dobrich, , Bulgaria

Investigational site

Pazardzhik, , Bulgaria

Investigational site

Pernik, , Bulgaria

Investigational Site

Pleven, , Bulgaria

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Plovdiv, , Bulgaria

Investigational site

Rousse, , Bulgaria

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Sofia, , Bulgaria

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Sofia, , Bulgaria

Investigational site

Sofia, , Bulgaria

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Sofia, , Bulgaria

Invesigational Site

Stara Zagora, , Bulgaria

Investigational Site

Varna, , Bulgaria

Investigational Site

La Serena, Coquimbo Region, Chile

Investigational Site

Temuco, Región de la Araucanía, Chile

Investigational Site

Barranquilla, Atlántico, Colombia

Investigational Site

Barranquilla, , Colombia

Investigational Site

Riga, , Latvia

Invetigational Site

Riga, , Latvia

Investigational Site

Ventspils, , Latvia

Investigational Site

Miri, Sarawak, Malaysia

Investigational Site

Alor Star, , Malaysia

Investigational Site

George Town, , Malaysia

Investigational Site

Kuala Lumpur, , Malaysia

Investigational Site

Kuala Lumpur, , Malaysia

Investigational Site

Taiping, , Malaysia

Investigational Site

Aguascalientes, , Mexico

Investigational Site

San Luis Potosí City, , Mexico

Investigational Site

Chorzów, , Poland

Investigational Site

Golub-Dobrzyń, , Poland

Investigational Site

Inowrocław, , Poland

Investigational Site

Katowice, , Poland

Investigational Drug

Pruszków, , Poland

Investigational Site

Bucharest, District 3, Romania

Investigational Site

Bucharest, , Romania

Investigational Site

Bucharest, , Romania

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Bucharest, , Romania

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Bucharest, , Romania

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Craiova, , Romania

Investigational Site

Slatina, , Romania

Investigational Site

Târgu Mureş, , Romania

Investigational Site

Kaluga, Russian Federation, Russia

Investigational Site

Krasnodar, Russian Federation, Russia

Investigational Site

Moscow, Russian Federation, Russia

Investigational Site

Nizhny Novgorod, Russian Federation, Russia

Investigational Site

Petrozavodsk, Russian Federation, Russia

Investigational Site

Saint Petersburg, Russian Federation, Russia

Investigational Site

Saint Petersburg, Russian Federation, Russia

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Saint Petersburg, Russian Federation, Russia

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Saint Petersburg, Russian Federation, Russia

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Smolensk, Russian Federation, Russia

Investigational Site

Moscow, Russian Ferderation, Russia

Investigational Site

Kolomna, , Russia

Investigational Site

Krasnodar, , Russia

investigational Site

Moscow, , Russia

Investigational Site

Novorossiysk, , Russia

Investigational site

Omsk, , Russia

Investigational Site

Orenburg, , Russia

Investigational Site

Rostov-on-Don, , Russia

Investigational Site

Saint Petersburg, , Russia

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Saint Petersburg, , Russia

Investigational Site

Saint Petersburg, , Russia

Investigational site

Goyang-si, Gyeonggi-do, South Korea

Investigational Site

Guri-si, Gyeonggi-do, South Korea

Investigational Site

Seongnam-si, Gyeonggi-do, South Korea

Investigational Site

Anyang-si, , South Korea

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Seoul, , South Korea

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Seoul, , South Korea

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Kaohsiung City, , Taiwan

Investigational Site,

New Taipei City, , Taiwan

Investigational Site

Taichung, , Taiwan

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Taichung, , Taiwan

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Bangkok, , Thailand

Investigational Site

Chiang Mai, , Thailand

Investigational Site

Ivano, Frankivisk, Ukraine

Investigational Site

Karkiev, , Ukraine

Investigational Site

Kiev, , Ukraine

Investigational Site

Mykolayiv, , Ukraine

Investigational Site

Ternopil, , Ukraine

Investigational Site

Zaporizhzhya, , Ukraine

Investigational Site

Zaporizhzhya, , Ukraine

Countries

United States; Argentina; Bulgaria; Chile; Colombia; Latvia; Malaysia; Mexico; Poland; Romania; Russia; South Korea; Taiwan; Thailand; Ukraine

References

Hamano T, Yamaguchi Y, Goto K, Martin S, Jiletcovici A, Dellanna F, Akizawa T, Barratt J. Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Four Global Roxadustat Phase 3 Trials. Adv Ther. 2024 Apr;41(4):1553-1575. doi: 10.1007/s12325-023-02728-2. Epub 2024 Feb 16.

Reference Type: DERIVED

PMID: 38363466 (View on PubMed)

Barratt J, Dellanna F, Portoles J, Choukroun G, De Nicola L, Young J, Dimkovic N, Reusch M. Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies. Adv Ther. 2023 Apr;40(4):1546-1559. doi: 10.1007/s12325-023-02433-0. Epub 2023 Feb 7.

Reference Type: DERIVED

PMID: 36749544 (View on PubMed)

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)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2013-002753-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

FGCL-4592-063

Identifier Type: -

Identifier Source: org_study_id