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

NCT02052310 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: FGCL-4592-0632013-002753-30
• Study Type: interventional
• Target: 1,043
• Locations: 15 countries
• Sites: 113

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.

Conditions

Anemia in Incident Dialysis Patients

Keywords

Anemia; Chronic Kidney Disease; Hemoglobin; End-Stage Renal Disease; Incident-Dialysis; Erythropoieitin; Erythropoieisis stimulating-agent; Roxadustat; AZD9941; ASP1517; FG4592

Outcome Measures

Primary Outcomes (2)

• US (FDA) Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (ITT Population)

  Hb values under the influence of rescue therapy were not censored for the primary analysis. Rescue therapy for roxadustat treated participants was defined as recombinant erythropoietin or analogue (erythropoiesis-stimulating agent \[ESA\]) or red blood cell (RBC) transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion. Baseline Hb was defined the mean of up to 4 last central lab values prior to the first dose of study treatment. The intermittent missing Hb data was 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 (Day 1, Week 0), Week 28 to 52

• Ex-U.S. Submission: Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (PPS Population)

  Hb response was defined, using central laboratory values, as: Hb ≥11.0 g/dL and a Hb increase from baseline by ≥1.0 g/dL in participants whose baseline Hb \>8.0 g/dL, or increase in Hb ≥2.0 g/dL in participants whose baseline Hb ≤8.0 g/dL. Rescue therapy for roxadustat treated participant was defined as recombinant erythropoietin or analogue (ESA) or RBC transfusion, and rescue therapy for epoetin alfa treated participants was defined as RBC transfusion.

  Baseline (Day 1, Week 0) up to Week 24

Secondary Outcomes (12)

• US (FDA Submission): Hb Responder Rate- Percentage of Participants Who Achieved a Hb Response at 2 Consecutive Visits at Least 5 Days Apart During First 24 Weeks of Treatment, Without Rescue Therapy Within 6 Weeks Prior to the Hb Response (ITT Population)

  Baseline (Day 1, Week 0) up to Week 24

• Ex-US Submission: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 52), Regardless of Rescue Therapy (PPS Population)

  Baseline (Day 1, Week 0), Week 28 to 52

• Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24

  Baseline (Day 1, Week 0), Week 12 to 24

• Mean Change From Baseline in Hb Levels Between Weeks 18 to 24 Regardless of Rescue Therapy in Participants Whose Baseline High Sensitivity C-Reactive Protein (Hs-CRP)> Upper Limit of Normal (ULN)

  Baseline (Day 1, Week 0), Week 18 to 24

• Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52

  Weeks 28 to 52

Study Arms (2)

Roxadustat

EXPERIMENTAL

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).

Drug: Roxadustat

Epoetin Alfa

ACTIVE COMPARATOR

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).

Drug: Epoetin Alfa

Interventions

Roxadustat DRUG

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

Also known as: ASP1517, AZD9941, FG-4592

Roxadustat

Epoetin Alfa DRUG

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

Also known as: Procrit, Epogen

Epoetin Alfa

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• Kyntra Bio: lead
• Astellas Pharma Europe B.V.: collaborator
• AstraZeneca: collaborator

Study Sites (113)

Investigational Site

Chula Vista, California, 91910, United States

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La Mesa, California, 91942, United States

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San Diego, California, 92111, United States

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Coral Springs, Florida, 33071, United States

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Lauderdale Lakes, Florida, 33313-1638, United States

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Miami, Florida, 33143, United States

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Miami, Florida, 33173, United States

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Tampa, Florida, 33614, United States

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Meridian

Meridian, Idaho, 83642, United States

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Shreveport, Louisiana, 71101, United States

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Detroit, Michigan, 48236, United States

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Pontiac, Michigan, 48341, United States

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Brookhaven, Mississippi, 39601, United States

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Columbus, Mississippi, 39705, United States

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Gulfport, Mississippi, 39501, United States

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Tupelo, Mississippi, 38801, United States

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Saint Ann, Missouri, 63074, United States

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St Louis, Missouri, 63136, United States

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Portsmouth, New Hampshire, 38815, United States

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Albuquerque, New Mexico, 87109, United States

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Durham, North Carolina, 27704, United States

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New Bern, North Carolina, 28562, United States

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Columbus, Ohio, 43215, United States

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Columbia, South Carolina, 29203, United States

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Orangeburg, South Carolina, 29118, United States

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Sumter, South Carolina, 29150, United States

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Knoxville, Tennessee, 37923, United States

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Edinburg, Texas, 78539, United States

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Houston, Texas, 77099, United States

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Houston, Texas, 77450, United States

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Serandi, Buenos Aires, 1872, Argentina

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Santa Fe, IX Region, S3000EPU, Argentina

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Burgas, 8000, Bulgaria

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Dobrich, 9300, Bulgaria

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Pazardzhik, 4400, Bulgaria

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Pernik, 2300, Bulgaria

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Pleven, 5800, Bulgaria

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Plovdiv, 4003, Bulgaria

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Rousse, 7000, Bulgaria

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Sofia, 1233, Bulgaria

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Sofia, 1407, Bulgaria

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Sofia, 1431, Bulgaria

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Sofia, 1504, Bulgaria

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Stara Zagora, 6000, Bulgaria

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Varna, 9000, Bulgaria

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La Serena, Coquimbo Region, 1720421, Chile

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Temuco, Región de la Araucanía, 4781151, Chile

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Barranquilla, Atlántico, Colombia

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Barranquilla, Colombia

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Riga, LV-1038, Latvia

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Riga, LV1001, Latvia

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Ventspils, LV3601, Latvia

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Miri, Sarawak, 98000, Malaysia

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Alor Star, 05460, Malaysia

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George Town, 10990, Malaysia

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Kuala Lumpur, 43000, Malaysia

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Kuala Lumpur, 50586, Malaysia

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Taiping, 34000, Malaysia

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Aguascalientes, 20230, Mexico

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San Luis Potosí City, 78240, Mexico

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Chorzów, 41-500, Poland

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Golub-Dobrzyń, 87-400, Poland

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Inowrocław, 88-100, Poland

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Katowice, 40-027, Poland

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Pruszków, 05-804, Poland

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Bucharest, District 3, 031422, Romania

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Bucharest, 020475, Romania

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Bucharest, 022305, Romania

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Bucharest, 022325, Romania

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Bucharest, 022329, Romania

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Craiova, 200349, Romania

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Slatina, 230108, Romania

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Târgu Mureş, 540098, Romania

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Kaluga, Russian Federation, 248007, Russia

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Krasnodar, Russian Federation, 350051, Russia

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Moscow, Russian Federation, 115446, Russia

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Nizhny Novgorod, Russian Federation, 603076, Russia

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Petrozavodsk, Russian Federation, 185019, Russia

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Saint Petersburg, Russian Federation, 191104, Russia

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Saint Petersburg, Russian Federation, 192242, Russia

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Saint Petersburg, Russian Federation, 193318, Russia

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Saint Petersburg, Russian Federation, 195257, Russia

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Smolensk, Russian Federation, 214006, Russia

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Moscow, Russian Ferderation, 125284, Russia

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Kolomna, 140407, Russia

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Krasnodar, 350029, Russia

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Moscow, 129327, Russia

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Novorossiysk, 353915, Russia

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Omsk, 644112, Russia

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Orenburg, 460040, Russia

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Rostov-on-Don, 142100, Russia

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Saint Petersburg, 194354, Russia

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Saint Petersburg, 196247, Russia

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Saint Petersburg, 197110, Russia

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Goyang-si, Gyeonggi-do, 410-719, South Korea

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Guri-si, Gyeonggi-do, 471-701, South Korea

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Seongnam-si, Gyeonggi-do, 463-712, South Korea

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Anyang-si, 431-796, South Korea

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Seoul, 130-872, South Korea

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Seoul, 134-727, South Korea

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Kaohsiung City, 83301, Taiwan

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New Taipei City, 235, Taiwan

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Taichung, 40447, Taiwan

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Taichung, 433, Taiwan

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Bangkok, 10330, Thailand

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Chiang Mai, 50200, Thailand

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Ivano, Frankivisk, 76008, Ukraine

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Karkiev, 61037, Ukraine

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Kiev, 02125, Ukraine

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Mykolayiv, 54058, Ukraine

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Ternopil, 46002, Ukraine

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Zaporizhzhya, 69118, Ukraine

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Zaporizhzhya, 69600, Ukraine

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Related Publications (3)

• 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.

  PMID: 38363466 DERIVED

• 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.

  PMID: 36749544 DERIVED

• 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.

  PMID: 36005278 DERIVED

MeSH Terms

Conditions

Anemia; Renal Insufficiency, Chronic; Kidney Failure, Chronic

Interventions

roxadustat; Epoetin Alfa

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Clinical Trial Information Desk
• Organization: FibroGen, Inc.

063study@fibrogen.com

415-978-1200

Study Officials

• Charles Bradley, PhD

  Kyntra Bio

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2014
• First Posted: February 3, 2014
• Study Start: February 11, 2014
• Primary Completion: September 21, 2018
• Study Completion: September 21, 2018
• Last Updated: October 1, 2021
• Results First Posted: October 1, 2021

Record last verified: 2021-09

Locations

UA (7); TH (2); US (30); LA (3); TW (4); PL (5); BU (13); MY (6); AR (2); ME (2); RU (21); CL (2); CO (2); KR (6); RO (8)