| Study characteristics |
| Methods |
|
| Participants |
General information
Setting: multicentre (31 sites) Country: Japan Inclusion criteria: Male and female Japanese participants aged ≥ 20 years; receiving chronic maintenance HD for kidney failure for at least 8 weeks prior to screening; for participants not being treated with ESAs: Hb < 10.0 g/dL, average of 2 measurements obtained during screening; for participants being treated with ESAs: Hb < 10.0 g/dL, average of 2 measurements obtained during screening after the protocol defined ESA washout period; serum ferritin ≥ 50 ng/mL during screening; TSAT ≥ 20% during screening; folate and vitamin B12 ≥ LLN during screening; for participants receiving oral and/or IV iron supplementation, the dose of iron supplementation had to be stable for at least 28 days prior to the screening period; for participants not receiving oral or IV iron supplementation, no iron supplementation was to have been administered for at least 28 days prior to the screening period; understood the procedures and requirements of the study and provided written informed consent and authorization for protected health information disclosure Exclusion criteria: anaemia due to a cause other than CKD or presence of active bleeding or recent blood loss; sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, haemolytic anaemia, thalassaemia, or PRCA; RBC transfusion within 4 weeks prior to or during screening; anticipated to recover adequate kidney function such that HD was no longer required during study participation; on PD or expected to change dialysis modality during study participation; hypo‐responsiveness to ESA defined as any of the following ESA treatments within 8 weeks prior to screening: (i) IV epoetin dose ≥ 3,000 units/dose 3 times/week, (ii) IV darbepoetin alfa dose ≥ 60 μg once/week, or (iii) EBP ≥ 200 μg once/month or ≥ 100 μg once every 2 weeks; AST/SGOT, ALT/SGPT, or total bilirubin > 2.0 times ULN during screening; uncontrolled hypertension (DBP > 110 mm Hg or SBP > 190 mm Hg) during screening; BMI > 42.0 kg/m²; severe heart failure during screening (NYHA class III or IV); history of untreated proliferative diabetic retinopathy, diabetic macular oedema, age‐related macular degeneration, central retinal vein occlusion, active retinal haemorrhage, or ongoing ocular treatment with laser photocoagulation or anti‐VEGF therapies; acute coronary syndrome (hospitalisation for unstable angina or MI), surgical or percutaneous intervention for coronary, cerebrovascular, or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalisation for heart failure, or stroke within 12 weeks prior to or during screening; history of active malignancy within 2 years prior to or during screening, except for treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps; history of DVT or pulmonary embolism requiring active treatment within 8 weeks prior to or during screening¹; history of haemosiderosis or haemochromatosis; history of prior organ transplantation or scheduled organ transplant, or prior haematopoietic stem cell or bone marrow transplant²; use of an investigational medication or participation in an investigational study within 30 days or 5 half‐lives of the investigational medication (whichever was longer), prior to screening; previous participation in a study with HIF‐PHI, other than vadadustat, within 90 days prior to screening; hypersensitivity to vadadustat, or to any of its excipients; pregnant or breast feeding; females of childbearing potential who were unable or unwilling to use an acceptable method of contraception; non‐vasectomized males who were unable or unwilling to use an acceptable method of contraception; any other reason that in the opinion of the investigator made the participant unsuitable for participation in the study Target Hb: 10 to 12 g/dL
Baseline characteristics
CKD stage: HD Number (randomised/analysed): treatment group 1 (15/15); treatment group 2 (15/15); treatment group 3 (15/14);control group (15/14) Mean age ± SD (years): treatment group 1 (not reported); treatment group 2 (not reported); treatment group 3 (not reported); control group (65.7 ± 11.6) Sex (M, %): overall (40, 69%); treatment group 1 (not reported); treatment group 2 (not reported); treatment group 3 (6, 43%) Time on dialysis (years): treatment group 1 (not reported); treatment group 2 (not reported); treatment group 3 (not reported); control group (7.6 ± 9.9) eGFR: not reported
Comorbidities (DD patients)
CV disease: not reported Heart disease: not reported Hypertension: not reported Diabetes (number, %): not reported Prior agents used (number, %): not reported
Note 1 from DD study: active treatment indicated treatment with an anticoagulant (blood thinner), such as heparin, enoxaparin, warfarin, rivaroxaban, apixaban, edoxaban, argatroban, and fondaparinux. Aspirin was not considered active treatment for DVT or pulmonary embolism
Note 2: subjects on kidney transplant wait list, or with a history of failed kidney transplant, corneal transplants, or stem cell therapy for knee arthritis were not excluded |
| Interventions |
Treatment group 1
Treatment group 2
Treatment group 3
Control group
Co‐interventions
|
| Outcomes |
Primary outcomes
Secondary outcomes
Mean change in Hb between pre‐treatment and the end of the dose adjustment and maintenance period (week 6) Mean Hb levels at week 6 and 16 Proportion who achieve Hb target at week 16 Mean change from baseline to week 6 and 16 in iron indices, TSAT, TIBC Proportion requiring rescue with RBC transfusion or ESAs at week 6 and 16 Changes in HCT, RBC count and reticulocytes count from baseline at week 6 and 16 Number of dose adjustments from baseline to week 6 and 16 Adverse events Serious adverse events Vital signs Laboratory evaluation
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| Notes |
Funding: Akebia Therapeutics Conflicts of interest: "M.N. has received honorarium, an advisory fee and research grant from Mitsubishi‐Tanabe and an advisory fee from Akebia Y.M.K.F., W.L., D.V. and Z.K. are employees of Akebia and Ed.G. was an employee of Akebia at the time of manuscript development" |
| 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 |
Unclear risk |
Quote: "Double‐blind"
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. 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 |
High risk |
Quote: "All participants were included in the safety population and 58 were included in the ITT population."
58/68 participants completed the full analysis (>5% lost to follow‐up), with differences between groups. Reasons were provided |
| Selective reporting (reporting bias) |
High risk |
All planned outcomes on ClincialTrials.gov have been measured and reported on in the final report
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 and authors' disclosure were reported
Funder was likely to influence data analysis and study reporting or interpretation |
