| Study characteristics |
| Methods |
Study design: phase 3, parallel RCT Time frame: March 2014 to June 2018 Duration of follow‐up: 2 years |
| Participants |
General information
Setting: multicentre (156 sites) Country: international (Austria, Belarus, Bulgaria, Croatia, Czech Republic, Finland, France, Georgia, Germany, Hungary, Ireland, Israel, Latvia, Montenegro, Netherlands, North Macedonia, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Ukraine, UK) Inclusion criteria: diagnosis of CKD KDOQI Stage 3, 4 or 5, not on dialysis; eGFR < 60 mL/min/1.73 m² estimated using MDRD equation; mean Hb ≤ 10.5 g/dL, with a difference of ≤ 1.0 g/dL; deemed suitable for treatment with ESA using the criteria specified in the KDIGO 2012 recommendation considering the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anaemia; serum folate ≥ LLN at screening; serum vitamin B12 ≥ LLN at screening; ALT and AST ≤ 3 times ULN, and total bilirubin ≤ 1.5 times ULN; weight 45.0 kg to 160.0 kg; males must not donate sperm starting from screening, throughout the study period and up to 12 weeks after final study drug administration Exclusion criteria: received any ESA treatment within 12 weeks prior to randomisation; received any dose of IV iron within 6 weeks prior to randomisation; received a RBC transfusion within 8 weeks prior to randomisation; subject has a known history of myelodysplastic syndrome or multiple myeloma; known hereditary haematologic disease such as thalassaemia or sickle cell anaemia, PRCA, or other known causes for anaemia other than CKD; known haemosiderosis, haemochromatosis, coagulation disorder, or hypercoagulable condition; known chronic inflammatory disease that could impact erythropoiesis (e.g. SLE, rheumatoid arthritis, coeliac disease) even if it is currently in remission; anticipated to undergo elective surgery that is expected to lead to significant blood loss during the study period or anticipated elective coronary revascularization; active or chronic GI bleeding; received any prior treatment with roxadustat or a HIF‐PHI; treated with iron‐chelating agents within 4 weeks prior to randomisation; history of chronic liver disease (e.g. cirrhosis or fibrosis of the liver); known NYHA class III or IV congestive heart failure; MI, acute coronary syndrome, stroke, seizure, or a thrombotic/thromboembolic event (e.g. DVT or pulmonary embolism) within 12 weeks prior to randomisation; one or more contraindications for treatment with darbepoetin alfa; uncontrolled hypertension, or 2 or more SBP ≥160 mm Hg or DBP ≥ 95 mm Hg within 2 weeks prior to randomisation; known hypersensitivity to darbepoetin alfa, rHuEPO, or any of the excipients; subject has a diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category 2F or higher) of renal cell carcinoma as shown on renal ultrasound within 12 weeks prior to randomisation; history of malignancy, except cancers determined to be cured or in remission ≥ 5 years, curatively basal cell or squamous cell skin cancers, cervical cancer in situ, or colonic polyps; positive for HIV, HBsAg or Anti‐HCV Ab; active clinically significant infection that is manifested by WBC > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection within 1 week prior to randomisation; known untreated proliferative diabetic retinopathy, diabetic macular oedema, macular degeneration or retinal vein occlusion; subject has had any prior organ transplant (that has not been explanted), subject is scheduled for organ transplantation, or subject is likely to initiate KRT including dialysis within the first year of the study; has received investigational therapy within 30 days or 5 half‐lives or limit set by national law, whichever is longer, prior to initiation of screening, condition which makes the subject unsuitable for study participation; an anticipated use of dapsone in any dose amount or chronic use of acetaminophen/paracetamol >2.0 g/day during the treatment or follow‐up period of the study; subject has a history of alcohol or drug abuse within 2 years prior to randomisation Target Hb: 10 to 12 g/dL
Baseline characteristics
CKD stage: CKD stages 3, 4, or 5 Number (randomised/analysed): treatment group (323/215); control group (293/209) ‐ ITT analysis Mean age ± SD (years): treatment group (66.8 ± 13.6); control group (65.7 ± 14.4) Sex (M, %): treatment group (145, 44.9%); control group (129, 44%) Time on dialysis (years): not applicable Mean eGFR ± SD (mL/min/1.73 m²): treatment group (20.31 ± 11.49); control group (20.34 ± 10.73)
Comorbidities
CV disease: not reported Heart disease: not reported Hypertension: not reported Diabetes (number, %): not reported -
Prior agents used (number, %)
ESA: treatment group (22/323); control group (17/293) IV iron: treatment group (47/323); control group (39/293) Oral iron: treatment group (142/323); control group (155/293)
|
| Interventions |
Treatment group (high dose)*
Roxadustat (ASP1517): 3 times/week Initial roxadustat dose from 70, 100 and 150 mg to 70 and 100mg; (maximum dose from 3.5 to 3.0 mg/kg and maximum absolute dose from 400 to 300 mg The mean SD weekly dose consumed was 223.20 (127.43) mg
Control group
Co‐interventions
*Note: dose assessed according to NCT01888445
|
| Outcomes |
Primary outcomes
Secondary outcomes
Hb change from baseline to the average Hb, without having received rescue therapy within 6 weeks prior to and during this 8‐week evaluation period (baseline and weeks 28 to 36) Change from baseline in LDL cholesterol to the average LDL cholesterol (baseline and weeks 12 to 28) Mean monthly IV iron (mg) use/subject (up to week 36) Change from baseline in SF‐36 Physical Functioning sub‐score to the average Physical functioning sub‐score (baseline and weeks 12 to 28) Change from in SF‐36 Vitality sub‐score to the average Vitality sub‐score (baseline and weeks 12 to 28) Change from baseline in MAP to the average MAP value (baseline and weeks 20 to 28) Occurrence of hypertension (up to week 36) Time to occurrence of hypertension (up to week 36) Hb change from baseline to the average Hb value regardless of rescue therapy (baseline and weeks 28 to 52) Time (weeks) to achieve the first Hb response as defined by primary endpoint Hb response (up to week 24) Hb averaged over weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy within 6 weeks prior to and during this evaluation period (up to week 104) Hb value to each post‐dosing time point to end of study (up to week 108) Hb change from baseline to each post‐dosing time point to end of study (up to week 108)] Hb change from baseline to the average Hb value regardless of the use of rescue therapy (weeks 28 to 36, weeks 44 to 52, weeks 72 to 80, weeks 96 to 104) Proportion of Hb values within 10.0 to 12.0 g/dL in weeks 28 to 36, 44 to 52, 72 to 80, 96 to 104, without use of rescue therapy within 6 weeks prior to and during the 8‐week evaluation period (up to week 104) Occurrence (number) of hospitalisation(s) (up to week 104) Number of days of hospitalisation (up to week 104) Number having received rescue therapy (composite of RBC transfusions (all subjects) and darbepoetin alfa use (roxadustat treated subjects only) (up to week 104) Number having received RBC transfusions (up to week 104) Number of RBC packs/subject (up to week 104) Volume of RBC transfused/subject (up to week 104) Change from baseline to each scheduled measurement in total cholesterol (baseline up to up to week 108) Change from baseline to each scheduled measurement in LDL/HDL ratio (baseline up to week 108) Change from baseline to each scheduled measurement in non‐HDL cholesterol (baseline up to week 108) Change from baseline to each scheduled measurement in Apo A1 (baseline up to week 108) Change from baseline to each scheduled measurement in ApoB (baseline up to week 108) Change from baseline to each scheduled measurement in ApoB/ApoA1 ratio (baseline (up to week 108) Occurrence of mean LDL cholesterol < 100 mg/dL (mean LDL calculated over weeks 12 to 28, and weeks 36 to 52 of treatment) (up to week 52) Occurrence of achieved anti‐hypertensive treatment goal (SBP < 130 mm Hg and DBP < 80 mm Hg) based on the mean SBP and mean DBP calculated over weeks 12 to 28 and 36 to 52 of treatment with study drug (up to week 52) Change from baseline to the average value in Physical Component Score of SF‐36 (baseline, weeks 12 to 28 and weeks 36 to 52) Change from baseline to the average value in Anemia Subscale ("Additional Concerns") of FACT‐Anaemia Score (baseline, weeks 12 to 28 and weeks 36 to 52) Change from baseline to the average value in Total FACT‐Anaemia score (baseline, weeks 12 to 28 and weeks 36 to 52) Change from baseline to the average value in EQ‐5D‐5L VAS score (baseline, weeks 12 to 28 and weeks 36 to 52) Change from baseline to the average value in WPAI‐Anemic Symptoms score (baseline, weeks 12 to 28 and weeks 36 to 52) PGIC (up to week 104) Change from baseline to each scheduled measurement serum ferritin (baseline up to week 108) Change from baseline to each scheduled measurement in TSAT (baseline up to week 108) Change from baseline to each scheduled measurement in HbA1c (baseline up to week 108) Change from baseline to each scheduled measurement in fasting blood glucose (baseline up to week 108) Change from baseline to each scheduled measurement in eGFR, including eGFR slope over time (baseline up to week 108) Change from baseline to each scheduled measurement in UACR (baseline up to week 108) Time to first of occurrence of SCr having doubled during study in comparison with baseline (baseline up to week 108) Occurrence of kidney failure (baseline up to week 108) Safety assessed by nature, frequency, and severity of treatment emergent adverse events (baseline up to week 108) Number of participants with laboratory value abnormalities and/or adverse events related to treatment (baseline up to week 108) Number of participants with vital signs abnormalities and/or adverse events related to treatment (baseline up to week 108) Safety assessed by 12‐ lead ECG (baseline up to week 108) Occurrence of prespecified adjudicated CV events (baseline up to week 108) Occurrence of prespecified adjudicated cerebrovascular events (baseline up to week 108)
|
| Notes |
Funding: Astellas Pharma Europe B.V., FibroGen Conflicts of interest: not reported -
Authors were contacted and extra information have been added to this review. Additional information are available at
|
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
Sequence generation methods were not reported in sufficient detail to permit judgement. It was not possible to assess if there was imbalance between intervention groups |
| Allocation concealment (selection bias) |
Unclear risk |
Method of allocation concealment was not reported in sufficient detail to permit judgement. It was not possible to assess if there was imbalance between intervention groups |
| Blinding of participants and personnel (performance bias)
All outcomes |
High risk |
Quote: "Open‐label" |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
Quote: "An Independent Review Committee was established to adjudicate cardiovascular events in a blinded manner." |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Quote: "Of 616 randomized pts (roxadustat, 323; DA, 293), 424 completed 2 years of treatment (roxadustat, 215; DA, 209)."
Quote: "A total of 424 [roxadustat group, n= 215 (66.6%); DA group, n= 209 (71.3%)] patients completed 2 years of treatment, whereas 33.4and 28.7% of patients discontinued treatment in the roxadustat and DA groups, respectively. Primary reasons for discontinuation in the roxadustat and DA groups were death [n= 27 (8.4%) versus n= 30 (10.2%)], withdrawal by patient [n= 32 (9.9%) versus n= 20 (6.8%)], progressive disease [n= 8 (2.5%) versus n= 15 ([5.1%)] and AEs [n= 21 (6.5%) versus n= 8] (2.7%)."
ITT on 322 participants in the intervention group and 292 participants in the control group |
| Selective reporting (reporting bias) |
Low risk |
All of the planned outcomes on ClincialTrials.gov were measured and reported on in the final report
Clinically‐relevant outcomes that would be expected for this type of intervention (death and CV events) were reported |
| Other bias |
High risk |
Baseline characteristics, or different non‐randomised co‐interventions were not reported between groups
Funder was likely to influence data analysis and study reporting or interpretation
Conflicts of interest were not reported |
