Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.

Anemia Clinical Trial

Official title:

A Phase 3, Multicenter, Randomized, Open-label, Active-Controlled Study of the Safety and Efficacy of Roxadustat in the Treatment of Anemia in Dialysis Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02174731
• Other study ID #: D5740C00002
• Status: Completed
• Phase: Phase 3
• Start date: July 1, 2014
• Est. completion date: September 26, 2018

Study information

• Verified date: November 2019
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in chronic kidney disease patients on dialysis.

Description:

This is a Phase 3, multicenter, randomized, open-label, active-controlled study to evaluate the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in dialysis patients. Patients on hemodialysis (HD) or peritoneal dialysis (PD) who have been treated with an erythropoietin analogue or have an indication for treatment with an erythropoietin analogue will be evaluated for eligibility and randomized at a 1:1 ratio to treatment with roxadustat (with discontinuation of prior erythropoietin analogue therapy) or to an active-control group treated with epoetin alfa

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2133
• Est. completion date: September 26, 2018
• Est. primary completion date: September 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion criteria:

1. Provision of Informed Consent prior to any study specific procedures

2. Age =18 years at screening visit 1

3. Previous versions of the protocol prior to US amendment ver 6.0 and outside of US amendment ver 7.0:

Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) at least 30 days prior to visit 1. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.

Starting with US amendment ver. 6.0 and outside of US amendment ver 7.0 (changed to recruit incident dialysis patients only):

Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) for a minimum of 2 weeks and a maximum of 4 months prior to randomization. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.

4. Two central laboratory Hb values during the screening period, obtained at least 7 days apart, must be <12 g/dL in patients currently treated with an erythropoietin analogue or <10 g/dL in patients not currently treated with an erythropoietin analogue. Patients are considered not currently treated if they have not received either Mircera® for at least 8 weeks or any other erythropoietin analogue for at least 4 weeks prior to visit 1.

5. Ferritin =100 ng/mL at randomization (obtained from screening visit)

6. TSAT =20% at randomization (obtained from screening visit)

7. Serum folate level = lower limit of normal (LLN) at randomization (obtained from screening visit)

8. Serum vitamin B12 level = LLN at randomization (obtained from screening visit)

9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =3x upper limit of normal (ULN), and total bilirubin (Tbili) =1.5 x ULN at randomization (obtained from screening visit)

10. Body weight 45 to 160 kg (prescribed dry weight)

Exclusion criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

2. Previous randomisation in the present study

3. New York Heart Association Class III or IV congestive heart failure at enrolment

4. Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization

5. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis or fibrosis of the liver)

6. Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a history of pure red cell aplasia or other known causes for anemia other than CKD

7. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis)

8. Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category IIF, III or IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. CT scan or MRI) conducted at screening or within 12 weeks prior to randomization.

9. Uncontrolled hypertension at the time of randomization (defined as systolic BP =180 mmHg or diastolic BP =100 mmHg on repeated measurement post-dialysis in hemodialysis patients or at any time in peritoneal dialysis patients), contraindication to epoetin alfa treatment (e.g., pure red cell aplasia, hypersensitivity or know inability to tolerate epoetin alfa)

10. History of prostate cancer, breast cancer or any other malignancy, except 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.

11. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)

12. Chronic inflammatory diseases such as rheumatoid arthritis, SLE, ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia

13. Known hemosiderosis, hemochromatosis or hypercoagulable condition

14. Any prior organ transplant with the exception of an autologous renal transplant or a renal transplant that was subsequently removed ("explanted") or scheduled organ transplantation date

15. Any red blood cell (RBC) transfusion during the screening period

16. Any current condition leading to active significant blood loss

17. Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)

18. Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within the month preceding the first administration of IP in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded)

19. History of alcohol or drug abuse within 2 years prior to randomization

20. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence (see Section 3.8)

21. Pregnant or breastfeeding females

22. Known allergy to the investigational product or any of its ingredients

23. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound efficacy or safety assessment, or may interfere with study participation

Related Conditions & MeSH terms

• Anemia

Intervention

Drug:
• Roxadustat
Roxadustat will be administered orally three times a week (TIW) to achieve an Hb level of 11 g/dL and maintain a Hb level of 11±1 g/dL.
• Epoetin alfa
Epoetin alfa will be administered TIW consistent with approved prescribing information for epoetin alfa to achieve an Hb level of 11 g/dL and maintain a Hb level of 11±1 g/dL.

Locations

Country	Name	City	State
Australia	Research Site	Camperdown
Australia	Research Site	Clayton
Australia	Research Site	Concord
Australia	Research Site	Launceston
Australia	Research Site	Prahan
Australia	Research Site	St Leonards
Australia	Research Site	Wahroonga
Bulgaria	Research Site	Botevgrad
Bulgaria	Research Site	Dupnitsa
Bulgaria	Research Site	Gotse Delchev
Bulgaria	Research Site	Haskovo
Bulgaria	Research Site	Razlog
Bulgaria	Research Site	Samokov
Bulgaria	Research Site	Sandanski
Bulgaria	Research Site	Shumen
Bulgaria	Research Site	Silistra
Bulgaria	Research Site	Sliven
Bulgaria	Research Site	Smolyan
Bulgaria	Research Site	Yambol
Canada	Research Site	Brampton	Ontario
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Greenfield Park	Quebec
Canada	Research Site	Kamloops	British Columbia
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Oshawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Saint John	New Brunswick
Canada	Research Site	Scarborough	Ontario
Canada	Research Site	Sydney	Nova Scotia
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Brno
Czechia	Research Site	Praha
Czechia	Research Site	Praha 4
Czechia	Research Site	Praha 4
Czechia	Research Site	Rychnov nad Kneznou
Czechia	Research Site	Slany
Czechia	Research Site	Tabor
Czechia	Research Site	Usti nad Labem
Hungary	Research Site	Ajka
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Miskolc
Hungary	Research Site	Nagykanizsa
Hungary	Research Site	Székesfehérvár
Hungary	Research Site	Tatabánya
India	Research Site	Chennai
India	Research Site	Ghaziabad NCR
India	Research Site	Hyderabad
India	Research Site	Kolkatta
India	Research Site	Lucknow
India	Research Site	Maharashtra
India	Research Site	Mumbai
India	Research Site	Mysore
India	Research Site	Nadiad
India	Research Site	New Delhi
India	Research Site	New Delhi
India	Research Site	Pune
India	Research Site	Vellore
India	Research Site	Vijayawada
Mexico	Research Site	Aguascalientes
Mexico	Research Site	Guadalajara
Mexico	Research Site	Mexico
Mexico	Research Site	Veracruz
Peru	Research Site	Lima
Peru	Research Site	Lima
Peru	Research Site	Lima
Philippines	Research Site	Cebu City
Philippines	Research Site	Iloilo
Philippines	Research Site	Iloilo City
Poland	Research Site	Ciechanów
Poland	Research Site	Katowice
Poland	Research Site	Konskie
Poland	Research Site	Lódz
Poland	Research Site	Lódz
Poland	Research Site	Pszczyna
Poland	Research Site	Suwalki
Poland	Research Site	Tarnów
Poland	Research Site	Warszawa
Russian Federation	Research Site	Arkhangelsk
Russian Federation	Research Site	Barnaul
Russian Federation	Research Site	Irkutsk
Russian Federation	Research Site	Izhevsk
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Nizhny Novgorod
Russian Federation	Research Site	Penza
Russian Federation	Research Site	Perm
Russian Federation	Research Site	Pyatigorsk
Russian Federation	Research Site	Ryazan
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Ufa
Slovakia	Research Site	Banska Bystrica
Slovakia	Research Site	Banska Bystrica
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Kosice
Slovakia	Research Site	Kralovsky Chlmec
Slovakia	Research Site	Nove Zamky
Slovakia	Research Site	Zvolen
Spain	Research Site	Almería
Spain	Research Site	Barcelona
Spain	Research Site	Granollers (Barcelona)
Spain	Research Site	Málaga
Spain	Research Site	Sevilla
Spain	Research Site	Sevilla
Spain	Research Site	Tarragona
Spain	Research Site	Valencia
Sweden	Research Site	Karlstad
Sweden	Research Site	Stockholm
Sweden	Research Site	Uppsala
Sweden	Research Site	Västerås
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Ukraine	Research Site	Chernivtsi
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Odesa
Ukraine	Research Site	Odesa
Ukraine	Research Site	Poltava
Ukraine	Research Site	Ternopil
Ukraine	Research Site	Uzhhorod
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Zaporizhzhya
Ukraine	Research Site	Zaporizhzhya
Ukraine	Research Site	Zaporizhzhya
United States	Research Site	Asheville	North Carolina
United States	Research Site	Austin	Texas
United States	Research Site	Austin	Texas
United States	Research Site	Baton Rouge	Louisiana
United States	Research Site	Bethlehem	Pennsylvania
United States	Research Site	Bluefield	West Virginia
United States	Research Site	Bronx	New York
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Denver	Colorado
United States	Research Site	East Providence	Rhode Island
United States	Research Site	El Centro	California
United States	Research Site	Fairfield	California
United States	Research Site	Glendale	California
United States	Research Site	Great Neck	New York
United States	Research Site	Gulfport	Mississippi
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Huntsville	Alabama
United States	Research Site	Kansas City	Missouri
United States	Research Site	Lanham	Maryland
United States	Research Site	Long Beach	California
United States	Research Site	Long Beach	California
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Lynwood	California
United States	Research Site	Miami Gardens	Florida
United States	Research Site	New Haven	Connecticut
United States	Research Site	Newport News	Virginia
United States	Research Site	Northridge	California
United States	Research Site	Ontario	California
United States	Research Site	Orange	California
United States	Research Site	Orchard Park	New York
United States	Research Site	Paterson	New Jersey
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Plymouth	Massachusetts
United States	Research Site	Reno	Nevada
United States	Research Site	River Forest	Illinois
United States	Research Site	Riverside	California
United States	Research Site	Roseville	Michigan
United States	Research Site	Sacramento	California
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	Shawnee	Oklahoma
United States	Research Site	Sterling	Virginia
United States	Research Site	Sun Valley	California
United States	Research Site	Whittier	California
United States	Research Site	Whittier	California
United States	Research Site	Wichita	Kansas
United States	Research Site	Wilmington	North Carolina
Vietnam	Research Site	Can Tho
Vietnam	Research Site	Hanoi
Vietnam	Research Site	Hochiminh
Vietnam	Research Site	Hue

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	FibroGen

Countries where clinical trial is conducted

United States,  Vietnam,  Australia,  Bulgaria,  Canada,  Czechia,  Hungary,  India,  Mexico,  Peru,  Philippines,  Poland,  Russian Federation,  Slovakia,  Spain,  Sweden,  Thailand,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52	Baseline Hb was defined as the mean of the three last central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to the participants mean level from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation Analysis of Covariance (ANCOVA). Baseline Hb was used as a covariate and treatment group, cardiovascular (CV) history, geographic region and dialysis duration as fixed effects. The adjusted least squares (LS) mean estimates of change from baseline during Week 28 to Week 52 are presented.	Baseline (Day 1, Week 0), Week 28 to 52
Secondary	Change in Hb From Baseline to the Mean Level During the Evaluation Period (Week 28 to Week 36) Without Having Received Rescue Therapy Within 6 Weeks Prior to and During the 8-Week Evaluation Period	Baseline Hb was defined as the mean of the three last central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to the participants mean level from Week 28 to Week 36,without having received rescue therapy within 6 weeks prior to and during this 8 week evaluation period was analysed using Mixed Model of Repeated Measures (MMRM). Baseline Hb was used as a covariate and treatment group, CV history, geographic region and dialysis duration as fixed effects. The adjusted LS mean estimates of change from baseline during Week 28 to Week 36 are presented for participants that did not receive rescue therapy within 6 weeks prior to and during this 8-week evaluation period.	Baseline (Day 1, Week 0), Week 28 to 36
Secondary	Proportion of Total Time of Hb Within the Interval of >=10 g/dL From Week 28 to Week 52	The proportion of total time was computed as follows: For each participant, the recorded Hb values were first linearly interpolated between measurements. The time this interpolated curve was >=10 g/dL was computed and subsequently divided by the time between the measurements from Week 28 to Week 52. The difference between roxadustat and epoetin alfa were compared using ANCOVA. Baseline Hb was used as a covariate and the treatment groups, CV history, geographic region and dialysis duration as fixed effects.	Week 28 to 52
Secondary	Proportion of Total Time of Hb Within the Interval of 10 to 12 g/dL From Week 28 to Week 52	The proportion of total time was computed as follows: For each participant, the recorded Hb values were first linearly interpolated between measurements. The time this interpolated curve was within 10-12 g/dL was computed and subsequently divided by the time between the measurement from Week 28 to 52. The difference between roxadustat and epoetin alfa were compared using ANCOVA. Baseline Hb was used as a covariate and the treatment groups, CV history, geographic region and dialysis duration as fixed effects.	Week 28 to 52
Secondary	Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24	Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analysed using ANCOVA. Baseline Hb and baseline LDL were used as covariates and treatment groups, CV history, geographic region and dialysis duration as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.	Baseline (Day 1, Week 0) to Week 24
Secondary	Mean Change in Hb From Baseline to the Participant's Mean Level Between Week 28 to Week 52 in Participants With Baseline High-Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN)	Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb is defined as the mean of the three last central laboratory Hb values from the screening and randomization visits. Changes in Hb from baseline to mean value during Weeks 28 to 52 in participants with baseline hsCRP >ULN was analyzed using a MAR based multiple imputation ANCOVA. Baseline Hb was used as a covariate and treatment group, CV history, geographic region and dialysis duration as fixed effects. The adjusted LS mean estimates of change from baseline during Week 28 to Week 52 are presented.	Baseline (Day 1, Week 0), Week 28 to 52
Secondary	Mean Monthly IV Iron Use From Week 36 to End of Study (EOS)	Oral iron supplementation was allowed for both treatment groups without restriction. Oral iron was recommended for dietary supplementation to support erythropoiesis and as the first line treatment for prevention and treatment of iron deficiency, unless the participant was intolerant to this route of treatment. In participants receiving roxadustat, the Investigator was allowed to initiate the use of an approved IV iron supplement if a participant's Hb value had not sufficiently responded to 2 or more dose increases of the IP, and ferritin <100 nanogram per milliliter (ng/mL) or transferrin saturation (TSAT) <20%. IP treatment was allowed to continue during IV iron administration. Discontinuation of IV iron supplementation was recommended once the participant was no longer considered to be iron deficient (ferritin >100 ng/mL and TSAT >20%).	Week 36 to EOS (4 weeks after the treatment period)
Secondary	Time-To-First Administration of RBC Transfusion as Rescue Therapy	Time-to-first RBC transfusion as rescue therapy was calculated as (date of first occurrence of any RBC transfusion as rescue therapy, or date of censoring if no event had occurred) - (date of first dose of IP) + 1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.	Baseline (Day 1, Week 0) up to EOS (4 weeks after the treatment period)

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