| Study characteristics |
| Methods |
Study design: parallel RCT Time frame: November 2014 to July 2018 Duration of follow‐up: 108 weeks (treatment period (minimum of 52 weeks, maximum of 104 weeks) and a post‐treatment follow‐up period of 4 weeks |
| Participants |
General information
Setting: multicentre (150 sites) Country: 17 countries including Belgium, Bulgaria, Croatia, Czech Republic, France, Georgia, Germany, Hungary, Italy, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, Spain, and UK Inclusion criteria: males or females aged ≥ 18 years who were on stable HD, HDF or PD for anaemia; received the same mode of dialysis for ≥ 4 months prior to randomisation; received treatment with IV or SC epoetin or darbepoetin alfa treatment for ≥ 8 weeks prior to randomisation, with stable weekly doses during 4 weeks prior to randomisation; mean of 3 most recent Hb values, as measured by central laboratory, during the screening period, obtained at least 4 days apart, were to be ≥ 9.5 g/dL and ≤ 12.0 g/dL with an absolute difference ≤ 1.3 g/dL between the highest and the lowest value Exclusion criteria: received a RBC transfusion within 8 weeks prior to randomisation; known hereditary haematologic disease such as thalassaemia or sickle cell anaemia, PRCA, or other known causes for anaemia other than CKD; MI, acute coronary syndrome, stroke, seizure, or a thrombotic/thrombo‐embolic event (e.g. DVT or pulmonary embolism) within 12 weeks prior to randomisation; uncontrolled hypertension, in the opinion of the investigator, within 2 weeks prior to randomisation; 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; any prior organ transplant (that has not been explanted), or participant is scheduled for organ transplantation Target Hb: 10 to 12 g/dL
Baseline characteristics
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CKD stage:
Number (randomised/analysed): treatment group (415/249); control group (423/309) Mean age ± SD (years): treatment group (61.0 ± 13.8); control group (61.8 ± 13.4) Sex (M, %): treatment group (245, 59.2%); control group (235, 56.0%) Time on dialysis: not reported eGFR: not reported
Comorbidities
CV disease: not reported Heart disease: not reported Hypertension: not reported Diabetes: treatment group (104/414); control group (133/420) -
Prior agents used (number, %)
|
| Interventions |
Treatment group (high dose)*
Control group
Co‐interventions
Oral iron treatment was recommended for supplementation to support erythropoiesis and as first‐line treatment for iron deficiency, unless participant was intolerant to this treatment. For participants receiving roxadustat the recommended daily dose was 200 mg of elemental iron. Participants were advised to take roxadustat at least 1 hour before or 1 hour after oral iron. IV iron supplementation for participants receiving roxadustat was allowed if all of the following criteria were met: Hb level had not responded adequately to roxadustat following two consecutive dose increases or reached the maximum dose limit, and ferritin was < 100 ng/mL (< 220 pmol/L) or TSAT < 20%, or they were intolerant of oral iron therapy. For participants treated with epoetin alfa or darbepoetin alfa, IV iron supplementation was given according to standard of care
*Note: dose assessed as high (mean dose 210 mg) according to NCT01888445
|
| Outcomes |
Primary outcomes
Change in Hb from baseline to the average level during the evaluation period (defined as week 28 until week 36), without having received rescue therapy (i.e., RBC transfusion for all patients or ESA for patients treated with roxadustat) within 6 weeks prior to and during this 8‐week evaluation period The USA (FDA) primary efficacy endpoint was change in Hb from baseline to the average level during the evaluation period (defined as week 28 until week 52), regardless of rescue therapy
Secondary outcomes
Hb response, defined as mean Hb during weeks 28 to 36 within the target range of 10.0 to 12.0 g/dL without having received rescue therapy within 6 weeks prior to and during this 8‐week evaluation period Change from baseline in LDL cholesterol to the average LDL cholesterol of weeks 12 to 28 Mean monthly IV iron use (mg) during day 1 to week 36 (monthly defined as a period of 4 weeks) Change from baseline in the SF‐36 Physical Functioning sub score to the average Physical Functioning sub score of weeks 12 to 28 Change from baseline in SF‐36 Vitality sub score to the average Vitality sub score of weeks 12 to 28 Change in MAP from baseline to the average MAP of weeks 20 to 28 and time to an increase in BP during weeks 1 to 36 Treatment‐emergent adverse events (TEAEs; frequency, severity, seriousness, and relationship to study drug), and pre‐specified adjudicated CV and cerebrovascular events (reported separately) Vital signs: SBP and DBP, heart rate, and respiratory rate Clinical laboratory variables: haematology, biochemistry including liver enzymes and total bilirubin, and urinalysis Physical examination 12‐lead ECG Vascular access thrombosis Hospitalisation SF‐36
|
| Notes |
Funding: Astellas Pharma Conflicts of interest: "U. Valluri is an employee of Astellas Pharma, Inc. M. Reusch is an employee of Astellas Pharma Europe B.V. J. Barratt, B. Csiky, C. Esposito, M. Schomig, and W. Sulowicz have nothing to disclose" Authors were contacted to request extra information but they did not reply |
| 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. There were no imbalance between intervention groups |
| Allocation concealment (selection bias) |
Unclear risk |
Method of allocation concealment was not reported in sufficient detail to permit judgement. There were no 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 |
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. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment |
| Incomplete outcome data (attrition bias)
All outcomes |
High risk |
Quote: "All data from site (2 patients randomized to the ESA treatment group) are excluded due to Good Clinical Practice (GCP) violations; therefore a total of 836 patients were considered randomized for analysis: 415 to the roxadustat treatment group and 421 to ESA."
Quote: "A total of 558 (66.7%) patients completed the study up to 2 years of treatment, 249 (60.0%)in the roxadustat treatment group and 309 (73.4%) in the ESA treatment group. Overall, 40.0% of patients in the roxadustat treatment group and 26.6% of patients in the ESA treatment group discontinued treatment up to 2 years. A total of 13.0% of patients withdrew due to death (14.9% roxadustat vs 11.2% ESA) and 9.1% withdrew by patient(12.0% vs 6.2%)."
Analyses were performed on different number of participants (> 5% lost to follow‐up with imbalance between the two groups) |
| Selective reporting (reporting bias) |
High risk |
All planned outcomes on ClincialTrials.gov were not measured and reported on in the final report. Reasons were not provided
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
Funding was reported and authors' disclosure were not reported
Funder was likely to influence data analysis and study reporting or interpretation
Conflicts of interest were reported |
