| Study characteristics |
| Methods |
Study design: parallel RCT Time frame: November 2013 to March 2015 Duration of follow‐up: 28 weeks (4 weeks treatment comparing HIF versus placebo, 20 weeks comparing HIF versus control (placebo group assumed EPO, as needed) plus 4 weeks follow‐up) |
| Participants |
General information
Setting: multicentre (67 sites, dialysis centres and hospitals) Country: 16 countries including Australia, Canada, Czech Republic, Denmark, France, Germany, Hungary, Japan, Korea, Norway, Poland, Russian Federation, Spain, Sweden, UK, USA Inclusion criteria: ≥ 18 years (week ‐4 verification only); females and males subjects (week ‐4 verification only); females: if of childbearing potential, must agree to use one of the approved contraception methods, from screening until completion of the follow‐up visit OR of non‐childbearing potential defined as pre‐menopausal females with a documented tubal ligation, hysterectomy, or oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea; females on HRT whose menopausal status is in doubt will be required to use one of the approved contraception methods if they wish to continue their HRT during the study. otherwise they must discontinue HRT to allow confirmation of post‐menopausal status prior to study enrolment; for most forms of HRT, at least 2 weeks must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT, following confirmation of their post‐menopausal status, they can resume use of HRT during the study without use of a contraceptive method; QTcB < 470 msec or QTcB < 480 msec in subjects with bundle branch block; CKD‐related criteria; HD 3 to 5 times/week for at least 4 weeks prior to week ‐4 screening through week 4. NOTE: Combination methods including HF or UF with HD are allowed however, the type of dialysis (HD, HDF or UF) should not change during the study; a Kt/V urea ≥ 1.2 based on a historical value obtained within the prior month in order to ensure the adequacy of dialysis. If Kt/V urea is not available, then an average of the last 2 URR values of at least 65% at week ‐4; baseline Hb of 9.0 to 11.5 g/dL (may rescreen in a minimum of 2 weeks); using the same rHuEPO (epoetin or their biosimilars, or darbepoetin) with total weekly doses varying by no more than 50% during the 4 weeks prior to week ‐4, at day 1 (randomisation), confirm that total weekly doses varied by no more than 50% during the screening period; may be on stable maintenance oral or IV (≤ 100 mg/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to week ‐4, during the screening phase, and through the first 4 weeks after randomisation Exclusion criteria: planned change from HD to PD within the study time period; pre‐emptive or scheduled kidney transplant; epoetin dose of ≥ 360 IU/Kg/week IV or ≥ 250 IU/kg/week SC or darbepoetin dose of ≥ 1.8 µg/kg/week IV or SC within the prior 8 weeks through day 1; use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through day 1; vitamin B12 ≤ LLN; folate < 2.0 ng/mL; ferritin < 100 ng/mL; TSAT outside of the reference range; MI or acute coronary syndrome within the 8 weeks prior to screening through day 1; stroke or TIA within the 8 weeks prior to week ‐4 screening through day 1; NYHA class III/IV heart failure diagnosed prior to week ‐4 screening through day 1; symptomatic right heart failure diagnosed prior to week ‐4 screening through day 1; hypertension (week ‐4, day 1) DBP) > 100 mm Hg) or SBP > 170 mm Hg; history of thrombotic disease within the 8 weeks prior to week ‐4 screening through day 1; meeting any ophthalmologic‐related exclusion criteria determined at the screening ophthalmology exam; active chronic inflammatory disease that could impact erythropoiesis (e.g. scleroderma, SLE, rheumatoid arthritis, coeliac disease) diagnosed prior to week ‐4 screening through day 1; any haematological disease including those affecting platelets, white or RBCs (e.g. sickle cell anaemia, myelodysplastic syndromes, haematological malignancy, myeloma, haemolytic anaemia and thalassaemia), coagulation disorders (e.g. antiphospholipid syndrome, protein C or S deficiency), or any other cause of anaemia other than kidney disease diagnosed prior to week ‐4 screening through day 1; current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or evidence at screening of abnormal liver function tests ALT or AST > 2.0 times ULN or total bilirubin > 1.5 times ULN; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study. NOTE: Those with Hepatitis B or Hepatitis C are eligible provided these exclusions are not met; Major surgery (excluding vascular access surgery) within the prior 8 weeks, during the week ‐4 screening phase or planned during the study; blood transfusion within the prior 8 weeks, during the week ‐4 screening phase or an anticipated need for blood transfusion during the study; evidence of actively bleeding peptic, duodenal, or oesophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks prior to week ‐4 screening through day 1; clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to week ‐4 screening through day 1 NOTE: IV antibiotics as prophylaxis are allowed; history of malignancy within the prior 5 years, who receiving treatment for cancer, or who have a strong family history of cancer (e.g. familial cancer disorders); with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to week ‐4 screening through day 1; history of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product; use of any prescription or non‐prescription drugs or dietary supplements that are prohibited from week ‐4 screening until the follow‐up visit; has participated in a clinical trial and has received an experimental investigational product within the prior 30 days from week ‐4 screening through day 1; any other condition, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk; pregnancy; an individual subject may not be rescreened more than twice; there is no predetermined amount of time that the investigator needs to wait to rescreen a previously ineligible subject, except those excluded for Hb or folate who may only rescreen in 2 and 4 weeks, respectively, and those excluded for Vitamin B12 who may rescreen in 8 weeks Target Hb: 10.0 to 11.50 g/dL
Baseline characteristics
CKD stage: 5D (HD) Number (randomised/analysed): treatment group (177/171); control group (39/39) Mean age ± SD (years): treatment group (59.6 ± 13.3); control group (59.7 ± 18.7) Sex (M, %): overall (134, 62%); treatment group (108, 63%); control group (26, 67%) Time on dialysis: not reported eGFR: not reported
Comorbidities
CVdisease: treatment group (166, 94%); control group (38, 97%) Heart disease: not reported Hypertension: treatment group (160, 90%); control group (37, 95%) Diabetes (number, %): treatment group (62, 35%); control group (18, 46%) Prior agents used (number, %): not reported
|
| Interventions |
Treatment group
Daprodustat (oral tablets): starting doses from 4, 6, 8, 10, or 12 mg Time: 4 weeks (the rest of the study was conducted changing the control group) Titrated at week 4 to achieve and maintain Hb 10 to 11.5 g/dL
Control group
Co‐interventions
|
| Outcomes |
Primary outcome
Secondary outcomes
Hb concentration at week 24 Percentage of time within, below and above Hb target range between weeks 20 to 24 Number (%) with Hb in the target range at week 24 Number (%) reaching predefined Hb stopping criteria Change from baseline in hepcidin, ferritin, transferrin, TSAT, total iron, TIBC, and CHr at week 24 Change from baseline in HCT, RBC count, and reticulocyte number at week 24 Maximum observed change from baseline in EPO Maximum observed change from baseline in VEGF Incidence and severity of adverse and serious adverse events Reasons for discontinuation of study medication Discontinuation for safety‐related reasons (prespecified stopping criteria or adverse events) until the end of follow‐up period Absolute values and changes from baseline in laboratory parameters, sPAP, left ventricular ejection fraction, ophthalmology assessments and vital signs Preliminary assessment of MACE and other CV events
|
| Notes |
Funding: GlaxoSmithKline Conflicts of interest: "A.M.M., B.C., N.B., D.J., J.J.L. and A.R.C. are employees of and hold stock in GlaxoSmithKline (GSK). L.H. and B.M.J. are former employees of GSK and hold stock options in GSK. A.K.N. received research grants from GSK and research sponsorship from Affymax. M.A. has no potential conflicts of interest to report. This manuscript is not under consideration for publication elsewhere. The results presented in this article have not been published previously in whole or part, except in abstract form. Some of the data included in the present article were presented at the American Society of Nephrology meeting in Chicago, IL, USA, 15–20 November 2016." |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Quote: "Participants were assigned to study treatment in accordance with a randomisation schedule that utilized central randomisation. The randomisation schedule was computer generated using the randomisation system RandAll"
Quote: "Eligible participants were stratified by region (Japan versus non‐Japan) and prior rhEPO dose and then randomized 2:2:2:2:1:2." |
| Allocation concealment (selection bias) |
Low risk |
Quote: "Participants randomized to daprodustat had automatic dose adjustments through an interactive voice/web response system based on a prespecified dose‐adjustment algorithm,"
Quote: "The response system managed by Perceptive, Nottingham, UK" |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Quote: "For the first 4 weeks, treatment was fully blinded to treatment group with control participants receiving placebo QD. Thereafter, only the dose of daprodustat was blinded, with control participants receiving standard‐of‐care open‐label rhEPO (epoetin or their biosimilars, or darbepoetin alfa) as required for the remaining 20 weeks to achieve haemoglobin within the target range (10‒11.5 g/dL)."
For the scope of this review, we considered only the first 4 weeks, where the comparison was clearly HIF vs placebo. The first 4 weeks were conducted in double blind |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
Quote: "An internal GlaxoSmithKline Safety Review Team reviewed blinded safety data in stream and an independent data monitoring committee periodically reviewed the same safety data but unblinded." |
| Incomplete outcome data (attrition bias)
All outcomes |
High risk |
Not reported in sufficient detail to perform adjudication in the first 4 weeks of the treatment. Overall, ITT performed on 171/177 participants in the intervention group. and 39/39 participants in the control group. Imbalance between the two groups |
| Selective reporting (reporting bias) |
High risk |
All pre‐specified outcomes were not reported, for the end of the 4th week where the intervention were compared only with placebo
Clinically‐relevant outcomes that would be expected for this type of intervention were not reported |
| Other bias |
High risk |
Stopped early due to some data‐dependent process (including a formal‐stopping rule)
Funder was likely to influence data analysis and study reporting or interpretation
Authors declared conflicts of interests |
