| Study characteristics |
| Methods |
Study design: 2‐arm, parallel RCT Time frame: December 2015 to June 2016 Duration of follow‐up: 27 weeks (treatment period 26 weeks, follow‐up 1 week) |
| Participants |
General information
Setting: multicentre (29 sites) Country: China Inclusion criteria: aged 18 to 75 years; voluntarily signed and dated an informed consent form, approved by an Ethics Committee, after the nature of the study had been explained and the subject had the opportunity to ask questions; a separate informed consent form was needed for subjects participating in the pharmacokinetic sub‐study; CKD with kidney failure on either adequate HD or adequate PD for a minimum of 16 weeks prior to day 1. For subjects undergoing HD, the vascular access must have been set up via native AVF or graft, or permanent, tunnelled catheter; must have been on stable doses of IV or SC injections of epoetin‐alfa for at least 6 weeks prior to day 1 (average dose ≤ 15,000 IU/week); mean of the 2 most recent central laboratory Hb values during the screening period, obtained at least 6 days apart, must have been 9.0 to 12.0 g/dL, inclusive, with a difference of ≤ 1.5 g/dL between the highest and the lowest Hb values; ALT and AST lower than 1.5 times ULN, and normal total bilirubin at the screening visit except for subjects with Gilberts syndrome (based on central laboratory results); weight 45 to 100 kg; agreed to not start taking any new TCM for anaemia and not to change dose, schedule, or brand of any prescreening TCM for anaemia from the beginning of the screening period through the end of the follow‐up period Exclusion criteria: any clinically significant infection or evidence of an active underlying infection; positive for any of the following: HIV, HBsAg, or anti‐HCV Ab; chronic liver disease; NYHA class III or IV congestive HF; MI, acute coronary syndrome, stroke, seizure, or a thromboembolic event (e.g. deep venous thrombosis or pulmonary embolism) within 52 weeks prior to day 1; uncontrolled hypertension in the opinion of the investigator; diagnosed or suspected renal cell carcinoma as shown on renal ultrasound during the screening period; 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, or in situ cancer at any site; chronic inflammatory disease other than GN that could have impacted erythropoiesis (e.g. SLE, rheumatoid arthritis, coeliac disease); clinically significant GI bleeding; known history of myelodysplastic syndrome, multiple myeloma, hereditary hematologic disease such as thalassaemia, sickle cell anaemia, PRCA, or other known causes for anaemia other than CKD, haemosiderosis, haemochromatosis, known coagulation disorder, or hypercoagulable condition; any prior functioning organ transplant or a scheduled organ transplantation, or anephric; anticipated elective surgery that could have led to significant blood loss during the study period; anticipated use of dapsone or acetaminophen > 2.0 g/day, or > 500 mg/dose repeated every 6 hours for more than 3 days; serum albumin < 2.5 g/dL; androgen, deferoxamine, deferiprone, or deferasirox therapy within 12 weeks prior to day 1; Life expectancy < 12 months; blood transfusion within 12 weeks prior to day 1 or anticipated need for transfusion; IV iron supplement during the screening period and/or unwilling to withhold IV iron; immune suppressive or systemic steroid treatment within 12 weeks prior to day 1; history of alcohol or drug abuse within the past 2 years and inability to avoid consumption of more than > 3 alcoholic beverages/day; prior treatment with FG‐4592 or any HIF prolyl hydroxylase inhibitor; use of an investigational medication or treatment, participation in an investigational interventional medication or treatment, or carryover effect of an investigational treatment expected during the study; pregnant or breastfeeding; women of childbearing potential and men with sexual partners of childbearing potential who are not using adequate contraception; any medical condition that, in the opinion of the investigator, posed a safety risk to a subject in this study, confounded efficacy or safety assessments, or interfered with study participation Target Hb: the lower boundary of the 95% CI for the treatment difference in the change in Hb level had to be per dL
Baseline characteristics
-
CKD stage: dialysis (HD and PD)
Number (randomised/analysed): treatment group (204/204); control group (101/100) Mean age ± SD (years): treatment group (47.6 ± 11.7); control group (51.0 ± 11.8) Sex (M, %): treatment group (126, 61.8%); control group (58, 58%) Time on dialysis (years): treatment group (4.5 ± 3.5 ); control group (4.4 ± 2.9) eGFR: not reported
Comorbidities
CVdisease: not reported Heart disease: not reported Hypertension: not reported Diabetes(number, %): not reported Prior agents used(number, %): not reported
|
| Interventions |
Treatment group (high dose)*
Roxadustat: starting dose was either 100 mg (in patients weighing 45 to < 60 kg) or 120 mg (in patients weighing ≥ 60 kg) The dose steps were as follows: 20, 40, 50, 70, 100, 120, 150, 200, and 250 mg. Dose adjusted according to change in Hb over last 4 weeks and current Hb. See supplementary Table 2; maximum dose 2.5 mg/kg. Dose adjusted to achieve Hb 10 to 12 g/dL in participants, 3 times/week for 26 weeks
Control group
Co‐interventions
*Note: dose assessed according to NCT01888445
|
| Outcomes |
Primary outcomes
Secondary outcomes
Proportion with a Hb response (defined as a mean Hb level, averaged over weeks 23 through 27, that was no lower than 1.0 g/dL below baseline) Proportion with a mean Hb level, averaged over weeks 23 through 27, of at least 10.0 g/dL Mean change from baseline in iron biomarker levels at week 27 First exacerbation of hypertension in a time‐to‐event analysis Mean change from baseline in the MAP measured before the start of a dialysis session, averaged over weeks 23 through 27
|
| Notes |
Funding: FibroGen and FibroGen [China] Medical Technology Development Conflicts of interest: Robert Leong, M.D., Chunrong Wang, M.D., Cameron Liu, Ph.D., Thomas Neff, Lynda Szczech, M.D., M.S.C.E., and Kin‐Hung P. Yu, M.D. are employees of FibroGen |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
Quote: “Randomisation was performed centrally in sequence, stratified according to the dose of epoetin alfa at baseline (<8000 IU or ≥8000 IU per week) and dialysis method (haemodialysis or peritoneal dialysis).”
Sequence generation methods were not reported in sufficient detail to permit judgement. However, no imbalance between intervention groups was apparent |
| 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: "This trial (FGCL‐4592‐806) was a randomized, open‐label, active‐controlled, phase 3 trial." |
| 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 |
Low risk |
Quote: “A total of 48 patients (42 in the roxadustat group and 6 in the epoetin alfa group) discontinued the assigned medication. A total of 256 patients (162 in the roxadustat group and 94 in the epoetin alfa group) completed treatment.”
256/304 (84%) participants completed the study according to the safety population. Reason for discontinuations were provided that seemed unrelated with the treatment assigned
Lost to follow‐up: < 5%
305 patients underwent randomisation (204 patients to the roxadustat group and 101 to the epoetin alfa group). One patient in the epoetin alfa group did not receive treatment, so 304 patients were included in the full analysis set (ITT population)
All participants were included in the ITT analysis |
| Selective reporting (reporting bias) |
Low risk |
Expected outcomes reported and correlate with the planned outcomes on ClincialTrials.gov.
Clinically‐relevant outcomes that would be expected for this type of intervention were reported (death and CV events). |
| Other bias |
High risk |
Quote: “The trial was designed by the first two authors and the sponsor (FibroGen). The sponsor provided financial support and was responsible for data collection and analysis.”
There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups
Funder was likely to influence data analysis and study reporting or interpretation
Authors declared conflicts of interest |
