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. 2022 Aug 25;2022(8):CD013751. doi: 10.1002/14651858.CD013751.pub2

SIERRAS 2021.

Study characteristics
Methods

  • Study design: phase III, parallel RCT

  • Time frame: January 2015 and September 2018

  • Duration of follow‐up: 52 weeks
Participants General information

  • Setting: multicentre (76 sites)

  • Country: multinational (USA, Puerto Rico)

  • Inclusion criteria: ≥ 18 years; receiving adequate dialysis using the same modality of dialysis for kidney failure for ≥ 3 months prior to and during screening (Amendment 1 only: incident dialysis subjects receiving dialysis for native kidney failure for ≥ 2 weeks but ≤ 4 months at the time of randomisation); receiving IV or SC ESA for ≥ 8 weeks prior to screening and on a stable ESA (≤ 30% change) dose during 4 weeks (8 weeks if on Mircera) prior to randomisation (Amendment 1 Only: incident dialysis subjects must be on ESA for ≥ 4 weeks prior to screening, mean of subject's 3 most recent Hb values must be ≥ 9.0 g/dL and ≤ 12.0 g/dL; with an absolute difference of ≤ 1.3 g/dL between the highest and the lowest value; Amendment 1 only: for incident dialysis subjects, mean of the 3 most recent central lab Hb values during the screening period must be ≥ 8.5 g/dL and ≤12.0 g/dL); ferritin ≥ 100 ng/mL; TSAT ≥ 20%; serum folate ≥ LLN, Vitamin B12 level ≥ LLN; ALT and AST ≤ 3 times ULN, total bilirubin ≤ 1.5 times ULN; weight 45 kg to 160 kg

  • Exclusion criteria: received an RBC transfusion within 8 weeks prior to randomisation; known history of myelodysplastic syndrome or multiple myeloma; known inherited disease such as thalassaemia or sickle cell anaemia or other known causes for anaemia other than CKD; known haemosiderosis, haemochromatosis, coagulation disorder, or hypercoagulable condition; known chronic inflammatory disease that could cause anaemia; anticipated surgery that is expected to cause blood loss; known GI bleeding; history of chronic liver disease (e.g. chronic infectious hepatitis, chronic auto‐immune liver disease, cirrhosis, or fibrosis of the liver); congestive heart failure (NYHA Class III or IV); had a heart attack, stroke, seizure, or a thrombotic/thromboembolic event (e.g. DVT or pulmonary embolism) within 12 weeks prior to participating in the study; uncontrolled high BP within 2 weeks prior to participating in the study; history of malignancy, except for 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 HIV, HBsAG, or anti‐HCV Ab; has had any prior organ transplant (that has not been explanted); known untreated conditions (proliferative diabetic retinopathy, diabetic macular oedema, macular degeneration or retinal vein occlusion)

  • Target Hb: 10 to 12 g/dL, also at least 10 g/dL (both targets were evaluated) ‐ the analyses reported here were related to the target at least 10 g/dL


Baseline characteristics

  • CKD stage: HD and PD

    • HD: treatment group (354/370); control group (16/371)

    • PD: treatment group (354/370); control group (17/371)

  • Number (randomised/analysed): treatment group (370/334 ITT); control group (371/337 ITT)

  • Mean age ± SD (years): treatment group (57.6 ± 13.6); control group (58.4 ± 13.3)

  • Sex (M, %): treatment group (187, 50.5%); control group (215, 58%)

  • Time on dialysis (years): treatment group (4 ± 3.5); control group (3.9 ± 3.8)

  • eGFR: not reported


Comorbidities

  • CVdisease: not reported

  • Heart disease: data on MI, stroke and congestive heart failure reported

  • Hypertension: treatment group (366/370); control group (367/371)

  • Diabetes: treatment group (250/370); control group (254/371)

  • Prior agents used (number, %):

    • EPO alfa: treatment group (290/370); control group (293/371)

    • Darbepoetin alfa: treatment group (65/370); control group (65/371)

    • Mircera: treatment group (14/370); control group (8/371)

    • Other: treatment group (1/370); control group (4/371)
Interventions Treatment group (high dose)*

  • Roxadustat (FG‐4592) (oral): starting doses were 70, 100, 150, or 200 mg 3 times/week based on the patient’s prescribed pre‐study ESA dose


Control group

  • Epoetin alfa (IV): 3 times/week


Co‐interventions

  • Not reported


*Note: dose assessed as high according to NCT01888445
Outcomes Primary outcome

  • The primary efficacy endpoint for USA is defined as each subject's Hb change from baseline to the average level during the evaluation period, defined as weeks 28 to 52


Secondary outcomes

  • USA (FDA) submission: the proportion of subjects with a mean Hb level ≥ 10.0 g/dL during the evaluation period (day 1 to week 52)

  • Ex‐USA submissions: Hb response (mean 10.0 to 12.0 g/dL), during weeks 28 to 36 without having received rescue therapy

  • Average monthly IV Iron use per subject (weeks 1 to 36)

  • Change from baseline in LDL (weeks 12 to 28)

  • Change from baseline in SF‐36 Physical Functioning sub‐score (weeks 20 to 28)

  • Change from baseline in SF‐36 Vitality sub‐score (weeks 20 to 28)

  • Effect on predialysis BP (weeks 1 to 36)
Notes

  • Funding: FibroGen, Astellas Pharma Europe B.V., AstraZeneca

  • Conflicts of interest: "CC serves on Advisory Boards for AstraZeneca and FibroGen and received research support for Akebia, AstraZeneca, FibroGen, and GlaxoSmithKline. RMK owns FibroGen stock. MB received grants from FibroGen during the conduct of the study. GS, CB, ME, RL, KGS, CL, LS, and KHPY are employees of FibroGen and hold stock and/or stock options in FibroGen. EM, DS, SLD, and MM have no conflicts of interest to disclose. Roxadustat is in clinical development for the treatment of anaemia of CKD in collaboration with Astellas Pharma and AstraZeneca."
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote: "Automated randomisation and treatment assignments were performed using an Interactive Web Response System."
Allocation concealment (selection bias) Low risk Quote: "The randomisation code was concealed in the IRT system managed by the third party vendor. In this setting, the sponsor, a site or a patient would not know the treatment assignment beforehand and could not predict the treatment assignment for the next patient in line."
Quote: "Automated randomisation and treatment assignments were performed using an Interactive Web Response System."
Blinding of participants and personnel (performance bias)
All outcomes High risk Quote: "Open label"
Blinding of outcome assessment (detection bias)
All outcomes High risk Objective and subjective outcomes were reported
Incomplete outcome data (attrition bias)
All outcomes Unclear risk ITT population 334/370 participants in the intervention group and 337/371 participants in the control group
The number of participants included in the safety population, full analysis set and per protocol set varied
Selective reporting (reporting bias) Low risk All planned outcomes on ClincialTrials.gov were measured and reported
Clinically‐relevant outcomes that would be expected for this type of intervention (death and CV events) were reported
Other bias High risk There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups
Funding influenced data analysis and study reporting or interpretation
Conflicts of interest were reported.