| Study characteristics |
| Methods |
Study design: parallel RCT Time frame: December 2015 to September 2016 Duration of follow‐up: 9 weeks |
| Participants |
General information
Setting: multicentre (29 sites) Country: China Inclusion criteria: aged 18 to 75 years; voluntarily signed and dated an informed consent form; diagnosis of CKD KDOQI Stage 3, 4, or 5, not receiving dialysis; with an eGFR < 60 mL/min/1.73 m² estimated using the MDRD equation; no use of an ESA for at least 5 weeks before randomisation; mean of the 2 most recent Hb values during the screening period, obtained at least 6 days apart, must have been ≥ 7.0 g/dL and < 10.0 g/dL; ALT and AST ≤ 1.5 times ULN, and normal total bilirubin at screening visits (based on central laboratory results); weight 40 to 100 kg; agreed not to start taking any new TCM for anaemia and not to change dose, schedule, or brand of any prescreening TCM for anaemia from beginning of screening period through end of follow‐up period without approval of the FibroGen China Medical Monitor 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 heart failure; 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: 10.0 g/dL, the second definition was increase from baseline of at least 1.0 g/dL in patients with a baseline Hb level ≥ 8.0 g/dL or an increase of at least 2.0 g/dL in patients with a baseline Hb level < 8.0 g/dL. However, in this review we have considered only the first definition
Baseline characteristics
CKD stage: stage 3, 4, or 5, not receiving dialysis; with an eGFR < 60 mL/min/1.73 m² Number (randomised/analysed): treatment group (102/101); control group (52/51) Mean age ± SD (years): treatment group (54.7 ± 13.3); control group (53.2 ± 13,1) Sex (M, %): overall (56, 36%); treatment group (36, 36%); control group (20, 39%) Time on dialysis: not applicable MeaneGFR±SD (mL/min/1.73 m²): treatment group (16.5 ± 8); control group (14.5 ± 7.6)
Comorbidities
CVdisease: not reported Heart disease: not reported Hypertension(number, %): treatment group (89, 88%); control group (41, 80%) Diabetes(number, %): treatment group (22, 22%); control group (16, 31%) -
Prior agents used(number, %)
|
| Interventions |
Treatment group (high dose)*
Control group
Co‐interventions
*Note: dose assessed according to NCT01888445
|
| Outcomes |
Primary outcome
Secondary outcomes
Proportion who achieve a confirmed Hb response (up to and including week 9) Proportion with mean Hb ≥10.0 g/dL (weeks 7 to 9) Mean change from baseline in LDL cholesterol averaged (weeks 7 to 9) Effect on iron metabolism: measurement of serum iron (week 9) SF‐36 physical functioning sub score measured in week 9 in the FAS subjects with baseline physical functioning sub score below 35 (week 9) Mean change from baseline in SF‐36 vitality sub score measured in week 9 in FAS subjects with baseline vitality sub score below 50 (week 9) Mean change from baseline in MAP (weeks 7 to 9) Proportion who received rescue therapy (composite of blood transfusion, ESA use, and IV iron) (up to week 9) Percent with treatment‐emergent adverse events or serious adverse events (week 1 up to week 53) Number with treatment‐emergent adverse events or serious adverse events (week 1 up to week 53) Changes from baseline in vital signs (week 1 up to week 53) Changes from baseline in ECG findings (week 1 up to week 53) Changes from baseline in clinical laboratory values (week 1 up to week 53) Proportion on rescue therapy (week 1 up to week 53) Time to rescue therapy from date of first dose (week 1 up to week 53)
|
| Notes |
Funding: FibroGen and FibroGen [China] Medical Technology Development Conflicts of interest: "X. Peng, H. Lin, A. Yin, Y. Tao, X. Liang, Z. Liu, L. Zuo, and Y. Liao report receiving lecture fees from FibroGen; R. Leong, C. Wang, and B.‐C. Liu, being employed by FibroGen; T. Neff, L. Szczech, and K.‐H. Yu, being employed by and having an equity interest in FibroGen; and T. Neff, holding a patent (8,614,204) on “Enhanced erythropoiesis and iron metabolism,” owned by FibroGen. No other potential conflict of interest relevant to this article was reported" |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
Quote: "Eligible patients were randomly assigned in a 2:1 ratio to receive roxadustat or placebo. Randomization was performed centrally and was stratified according to the use or nonuse of an erythropoiesis‐stimulating agent within 12 weeks before randomisation and according to the estimated glomerular filtration rate (GFR) (<20 ml or ≥20 ml per minute per 1.73 m2 of body‐surface area)."
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. No imbalance between intervention groups was apparent |
| Blinding of participants and personnel (performance bias)
All outcomes |
Unclear risk |
Quote: "Double‐blind phase"
Although author reported that the study used a double‐blind design, information about blinding of participants and investigators were not clearly stated. However, since interventions were different, it was possible that investigators and/or participants were aware of treatment allocation. In the treatment groups were reported side effects that participants and/or investigators could know to be specific for one of the interventions. Possible deviations from the intended intervention that arose from the trial context were not reported |
| 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: "One patient in each group discontinued participation in the trial because of hyperkalaemia." "2 [participants] did not receive a trial regimen. One patient in the safety population took one dose of placebo and was lost to follow‐up"
151/154 participants completed the study according to the intention‐to‐treat population and 152/154 participants completed the study according to the safety population
Loss to follow‐up: < 5%, without differences between groups
Reason for discontinuations were provided that seemed unrelated with the treatment assigned |
| Selective reporting (reporting bias) |
High risk |
Not all of the planned outcomes on ClincialTrials.gov have been measured and reported on in the final report. No reasoning provided
Clinically‐relevant outcomes that would be expected for this type of intervention were not reported |
| Other bias |
High risk |
Quote: "The first two authors designed the trial in collaboration with representatives of the sponsor, FibroGen; company representatives were responsible for the collection and analysis of the data."
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 |
