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

ANDES 2021.

Study characteristics
Methods

  • Study design: parallel RCT

  • Time frame: November 2012 to September 2018

  • Duration of follow‐up: minimum treatment duration may be less than 52 weeks, with a maximum treatment duration of up to 3 years + 4 weeks follow‐up
Participants General information

  • Setting: multicentre (163 sites)

  • Country: international (USA, Argentina, Australia, Chile, Colombia, Hong Kong, Korea, Malaysia, New Zealand, Peru, Philippines, Puerto Rico, Singapore, Taiwan, Thailand)

  • Inclusion criteria: CKD stage 3, 4, or 5 not receiving dialysis; Adults  with eGFR < 60 mL/min/1.73 m²; Hb ≤ 10.0 g/dL, ferritin ≥ 30 ng/mL, and TSAT ≥ 5%; anaemia qualified by measurements of Hb values during screening; additional blood work must be in a safe range for study entry; body weight 45 to 160 kg; willingness to use contraception if of child‐bearing potential

  • Exclusion criteria: treatment with an ESA within 12 weeks prior to study participation; more than one dose of IV iron within 12 weeks prior to study participation; blood transfusion within 8 weeks prior to study participation; active infection; chronic liver disease; severe congestive HF; recent heart attack, stroke, seizure, or blood clot; uncontrolled BP within 2 weeks prior to study participation; renal cell carcinoma; history of malignancy, including multiple myeloma or other myelodysplastic syndrome; chronic inflammatory disease that could impact RBC production; any prior organ transplant, or a scheduled organ transplantation; anticipated elective surgery that is expected to lead to significant blood loss, or anticipated elective heart procedure; GI bleeding; any prior treatment with FG‐4592 or a HIF‐PHI; recent use of an investigation drug or treatment, or participation in an investigation study; > 1 IV iron dose; RBC transfusion within 8 weeks of randomisation

  • Target Hb

    • Baseline > 8.0 g/dL: ≥ 11 g/dL and an increase of ≥ 1.0 g/dL

    • Baseline ≤ 8.0 g/dL: ≥ 11 g/dL and an increase ≥ 2.0 g/dL


Baseline characteristics

  • CKD stage: stage 3, 4, or 5 not receiving dialysis

  • Number (randomised/analysed): treatment group (616/616); control group (306/306)

  • Mean age ± SD (years): treatment group (64.9 ± 12.6); control group (64.8 ± 13.2)

  • Sex (M, %): treatment group (241, 39.1%); control group (176, 42.5%)

  • Time on dialysis: not applicable

  • eGFR (mL/min/1.73 m²): treatment group (21.9 ± 11.5); control group (22.4 ± 11.4)


Comorbidities

  • CVdisease: not reported

  • Heart disease: not reported

  • Hypertension: treatment group (583, 94.6%); control group (292, 95.4%)

  • Diabetes (number, %): treatment group (398, 64.6%); control group (200, 65.4%)

  • Prior agents used (number, %): not reported
Interventions Treatment group (medium dose)*

  • FG‐4592 (Roxadustat) (oral): weight‐based starting doses of 70 mg or 100 mg, 3 times/week

    • Dose was titrated to achieve a Hb level ≥ 11 g/dL, followed by titration for maintenance

    • Patients weighing 45 to < 70 kg received 70 mg roxadustat or placebo, and those weighing ≥ 70 kg received 100 mg


Control group

  • Placebo


Co‐interventions

  • Oral iron was encouraged


*Note: dose assessed according to NCT01888445
Outcomes Primary outcome

  • Efficacy of roxadustat in achieving Hb correction and maintenance (52 weeks)


Secondary outcomes

  • Change in LDL cholesterol (28 weeks)

  • Evaluate HRQoL benefits, as measured by SF‐36 (28 weeks)

  • Proportion who received rescue therapy (composite of RBC transfusion, ESA use, and IV iron) (52 weeks)

  • Change in MAP and effect on reducing hypertension (52 weeks)

  • Adverse events, serious adverse events, vital signs, ECG and physical exams (minimum of 52 weeks)

  • Laboratory parameters (minimum of 52 weeks)

  • Death occurred during the study
Notes

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

  • Conflicts of interest: "DWC is a consultant for FibroGen, AstraZeneca, Vifor Pharma, GSK, Akebia, and FMC‐RTG. SDR has received travel fees for investigator meetings and honoraria for serving on advisory boards for FibroGen, AstraZeneca, ZS Pharma, Vifor Pharma, and Amgen. TMC is an employee of the University of Hong Kong, and he has consulted for Novartis, Visterra, and UCB Biosciences. He has received research funding from Astellas Pharma and Baxter. AAC receives research funding from FibroGen. AB is consultant to FibroGen. WC, CB, ME, RL, TL, LS and K‐HPY are employees of FibroGen, Inc. and hold stock and/or stock options in FibroGen, Inc. SGK, SKS, and MAM have no conflicts of interest to disclose"
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote: "Randomization schedules were prospectively prepared, and automated randomisation and treatment assignments were provided by an interactive web response system."
Allocation concealment (selection bias) Low risk Quote: "Randomization schedules were prospectively prepared, and automated randomisation and treatment assignments were provided by an interactive web response system."
Blinding of participants and personnel (performance bias)
All outcomes Low risk Quote: "Double‐blind study"
Quote: "The investigator, study site staff, patient, sponsor, and designees were all blinded to the study drug assignment—but not the dose—which was achieved by using identical roxadustat and placebo
Blinding of outcome assessment (detection bias)
All outcomes High risk Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. Reporting of some outcomes (adverse effects) were unlikely to be biased because outcome assessors were blinded to treatment assignment
Incomplete outcome data (attrition bias)
All outcomes Low risk Quote: "In the roxadustat group, 43.3% (267/616) of patients discontinued treatment, while 68.0% (208/306) of placebo‐treated patients discontinued. This between‐group difference in discontinuations was largely due to the lack of efficacy among patients in the placebo group. The primary reasons for discontinuations in the placebo group were withdrawal of consent and lack of efficacy. The primary reasons for discontinuations in the roxadustat group which occurred a lesser rates were adverse events or death and withdrawal of consent."
All participants were included in the ITT analysis 
Selective reporting (reporting bias) High risk All of the planned outcomes on ClincialTrials.gov were not measured and reported on in the final report
Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias High risk There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups
Quote: "FibroGen employees and subcontractors had a role in study design, data collection, data analysis, data interpretation, and writing of the manuscript."
Funder influenced data analysis and study reporting or interpretation
Authors declared conflicts of interest