Clinical trial NCT02052310: Safety and Efficacy Study of Roxadustat (FG-4592) for the Treatment of Anemia in End-Stage Renal Disease (ESRD) Newly Initiated Dialysis Participants
Official title: A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of the Efficacy and Safety of FG-4592 in the Treatment of Anemia in Incident-Dialysis Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: FibroGen
Sponsor class: INDUSTRY
Collaborators: name: Astellas Pharma Europe B.V.
name: AstraZeneca
First posted: 2014-02-03
Enrollment: 1043
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: 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)
timeFrame: Baseline (Day 1, Week 0), Week 28 to 52
measure: 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)
timeFrame: Baseline (Day 1, Week 0) up to Week 24
Secondary outcomes:
measure: 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)
timeFrame: Baseline (Day 1, Week 0) up to Week 24
measure: 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)
timeFrame: Baseline (Day 1, Week 0), Week 28 to 52
measure: Mean Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol Averaged Over Weeks 12 to 24
timeFrame: Baseline (Day 1, Week 0), Week 12 to 24
measure: 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)
timeFrame: Baseline (Day 1, Week 0), Week 18 to 24
measure: Median Monthly IV Iron Use Per Patient-Exposure-Month (PEM) During Weeks 28 to 52
timeFrame: Weeks 28 to 52
measure: Time to First RBC Transfusion
timeFrame: Baseline (Day 1, Week 0) up to last dose of study drug (maximum treatment duration was 227.9 weeks for roxadustat and 226.9 weeks for epoetin alfa)
measure: Mean Change From Baseline in Mean Arterial Pressure (MAP) Averaged Over Weeks 8 to 12
timeFrame: Baseline (Day 1, Week 0), Weeks 8 to 12
measure: Time to First Exacerbation of Hypertension During Weeks 28 to 52
timeFrame: Weeks 28 to 52
measure: Percentage of Participants With Exacerbation of Hypertension During Weeks 28 to 52
timeFrame: Weeks 28 to 52
measure: Time to Achieve the First Hb Response up to Week 24 Censoring for Rescue Therapy
timeFrame: Baseline (Day 1, Week 0) up to Week 24
measure: Percentage of Participants With Hb ≥10.0 g/dL Averaged Over Weeks 28 to 36 and 28 to 52, Regardless of Rescue Therapy
timeFrame: Weeks 28 to 36 and 28 to 52
measure: Mean Hb Change From Baseline to The Average Level During The Evaluation Period (Week 28 to Week 36), Censoring for Rescue Therapy
timeFrame: Baseline (Day 1, Week 0), Week 28 to 36
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: Investigational Site
state: California
city: La Mesa
country: United States
facility: Investigational Site
state: California
city: San Diego
country: United States
facility: Investigational Site
state: California
city: Coral Springs
country: United States
facility: Investigational Site
state: Florida
city: Lauderdale Lakes
country: United States
facility: Investigational Site
state: Florida
city: Miami
country: United States
facility: Investigational Site
state: Florida
city: Miami
country: United States
facility: Investigational Site
state: Florida
city: Tampa
country: United States
facility: Investigational Site
state: Florida
city: Meridian
country: United States
facility: Meridian
state: Idaho
city: Shreveport
country: United States
facility: Investigational Site
state: Louisiana
city: Detroit
country: United States
facility: Investigational Site
state: Michigan
city: Pontiac
country: United States
facility: Investigational Site
state: Michigan
city: Brookhaven
country: United States
facility: Investigational Site
state: Mississippi
city: Columbus
country: United States
facility: Investigational Site
state: Mississippi
city: Gulfport
country: United States
facility: Investigational Site
state: Mississippi
city: Tupelo
country: United States
facility: Investigational Site
state: Mississippi
city: Saint Ann
country: United States
facility: Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: Investigational Site
state: Missouri
city: Portsmouth
country: United States
facility: Investigational Site
state: New Hampshire
city: Albuquerque
country: United States
facility: Investigational Site
state: New Mexico
city: Durham
country: United States
facility: Investigational Site
state: North Carolina
city: New Bern
country: United States
facility: Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: Investigational Site
state: Ohio
city: Columbia
country: United States
facility: Investigational Site
state: South Carolina
city: Orangeburg
country: United States
facility: Investigational Site
state: South Carolina
city: Sumter
country: United States
facility: Investigational Site
state: South Carolina
city: Knoxville
country: United States
facility: Investigational Site
state: Tennessee
city: Edinburg
country: United States
facility: Investigational Site
state: Texas
city: Houston
country: United States
facility: Investigational Site
state: Texas
city: Houston
country: United States
facility: Investigational Site
state: Texas
city: Serandi
country: Argentina
facility: Investigational Site
state: Buenos Aires
city: Santa Fe
country: Argentina
facility: Investigational Site
state: IX Region
city: Burgas
country: Bulgaria
facility: Investigational Site
city: Dobrich
country: Bulgaria
facility: Investigational site
city: Pazardjik
country: Bulgaria
facility: Investigational site
city: Pernik
country: Bulgaria
facility: Investigational site
city: Pleven
country: Bulgaria
facility: Investigational Site
city: Plovdiv
country: Bulgaria
facility: Investigational Site
city: Ruse
country: Bulgaria
facility: Investigational site
city: Sofia
country: Bulgaria
facility: Investigational Site
city: Sofia
country: Bulgaria
facility: Investigational Site
city: Sofia
country: Bulgaria
facility: Investigational site
city: Sofia
country: Bulgaria
facility: Investigational Site
city: Stara Zagora
country: Bulgaria
facility: Invesigational Site
city: Varna
country: Bulgaria
facility: Investigational Site
city: Temuco
country: Chile
facility: Investigational Site
state: IX Region
city: La Serena
country: Chile
facility: Investigational Site
state: Region De Coquimbo
city: Barranquilla
country: Colombia
facility: Investigational Site
state: Atlántico
city: Barranquilla
country: Colombia
facility: Investigational Site
city: Goyang-Si
country: Korea, Republic of
facility: Investigational site
state: Gyeonggi-do
city: Guri-si
country: Korea, Republic of
facility: Investigational Site
state: Gyeonggi-do
city: Seongnam-si
country: Korea, Republic of
facility: Investigational Site
state: Gyeonggi-do
city: Anyang-si
country: Korea, Republic of
facility: Investigational Site
city: Seoul
country: Korea, Republic of
facility: Investigational Site
city: Seoul
country: Korea, Republic of
facility: Investigational Site
city: Riga
country: Latvia
facility: Investigational Site
city: Riga
country: Latvia
facility: Invetigational Site
city: Ventspils
country: Latvia
facility: Investigational Site
city: Miri
country: Malaysia
facility: Investigational Site
state: Sarawak
city: Alor Setar
country: Malaysia
facility: Investigational Site
city: George Town
country: Malaysia
facility: Investigational Site
city: Kuala Lumpur
country: Malaysia
facility: Investigational Site
city: Kuala Lumpur
country: Malaysia
facility: Investigational Site
city: Taiping
country: Malaysia
facility: Investigational Site
city: Aguascalientes
country: Mexico
facility: Investigational Site
city: San Luis Potosi
country: Mexico
facility: Investigational Site
city: Chorzów
country: Poland
facility: Investigational Site
city: Golub-Dobrzyń
country: Poland
facility: Investigational Site
city: Inowroclaw
country: Poland
facility: Investigational Site
city: Katowice
country: Poland
facility: Investigational Site
city: Pruszkow
country: Poland
facility: Investigational Drug
city: Bucharest
country: Romania
facility: Investigational Site
state: District 3
city: Bucharest
country: Romania
facility: Investigational Site
city: Bucharest
country: Romania
facility: Investigational Site
city: Bucharest
country: Romania
facility: Investigational Site
city: Bucharest
country: Romania
facility: Investigational Site
city: Craiova
country: Romania
facility: Investigational Site
city: Slatina
country: Romania
facility: Investigational Site
city: Targu- Mures
country: Romania
facility: Investigational Site
city: Moscow
country: Russian Federation
facility: Investigational Site
state: Russian Ferderation
city: Kaluga
country: Russian Federation
facility: Investigational Site
city: Kolomna
country: Russian Federation
facility: Investigational Site
city: Krasnodar
country: Russian Federation
facility: Investigational Site
city: Krasnodar
country: Russian Federation
facility: Investigational Site
city: Moscow
country: Russian Federation
facility: Investigational Site
city: Moscow
country: Russian Federation
facility: investigational Site
city: NIzhny Novgorod
country: Russian Federation
facility: Investigational Site
city: Novorossiysk
country: Russian Federation
facility: Investigational Site
city: Omsk
country: Russian Federation
facility: Investigational site
city: Orenburg
country: Russian Federation
facility: Investigational Site
city: Petrozavodsk
country: Russian Federation
facility: Investigational Site
city: Rostov-on-Don
country: Russian Federation
facility: Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site
city: Smolensk
country: Russian Federation
facility: Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Investigational site
city: St. Petersburg
country: Russian Federation
facility: Investigational Site
city: Kaohsiung
country: Taiwan
facility: Investigational Site
city: New Taipei City
country: Taiwan
facility: Investigational Site,
city: Taichung
country: Taiwan
facility: Investigational Site
city: Taichung
country: Taiwan
facility: Investigational Site
city: Bangkok
country: Thailand
facility: Investigational Site
city: Chiang Mai
country: Thailand
facility: Investigational Site
city: Ivano
country: Ukraine
facility: Investigational Site
state: Frankivisk
city: Karkiev
country: Ukraine
facility: Investigational Site
city: Kiev
country: Ukraine
facility: Investigational Site
city: Mykolayiv
country: Ukraine
facility: Investigational Site
city: Ternopil
country: Ukraine
facility: Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: Investigational Site
city: ZAporizhzhya
country: Ukraine
facility: Investigational Site
Study officials:
affiliation: FibroGen
name: Charles Bradley, PhD
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.