| Study characteristics |
| Methods |
|
| Participants |
General information
Setting: multicentre (30 sites) Country: Japan Inclusion criteria: males and females aged ≥ 20 years; diagnosis of CKD based on an eGFR ≤ 60 mL/min/1.73 m² (using the 2009 Japanese Society of Nephrology equation; Hb ≤ 10.5 g/dL during screening; not currently being treated with dialysis and not expected to start dialysis within 3 months of screening; serum ferritin ≥ 50 ng/mL during screening; TSAT ≥ 20% during screening; folate and vitamin B12 ≥ LLN during screening; for participants who were 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 who were 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, haematologic malignancy, myeloma, haemolytic anaemia, thalassaemia, or PRCA; RBC transfusion within 4 weeks prior to or during screening; IV iron within 4 weeks prior to or during screening; any ESA use within 6 weeks prior to or during screening (e.g. rHuEPO, darbepoetin alfa, or methoxy polyethylene glycol‐epoetin beta); AST/SGOT, ALT/SGPT, or total bilirubin >2.0 times ULN during screening; uncontrolled hypertension (confirmed DBP > 110 mm Hg or SBP > 180 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: eGFR ≤ 60 mL/min/1.73 m²; only one participant was Stage 3a (150 mg vadadustat group), with the remaining participants in Stage 3b–5 Number (randomised/analysed): treatment group 1 (12/12); treatment group 2 (12/12); treatment group 3 (13/13); control group (14/14) Mean age ± SD (years): treatment group 1 (not reported); treatment group 2 (not reported); treatment group 3 (not reported); control group (71.4 ± 11.6) Sex (M, %): overall (29, 57%); treatment group 1 (not reported); treatment group 2 (not reported); treatment group 3 (not reported); control group (4, 29%) Time on dialysis: not applicable Mean eGFR ± SD (mL/min/1.73 m²): treatment group 1 (not reported); treatment group 2 (not reported); treatment group 3 (not reported); control group (22.0 ± 9.8)
Comorbidities
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
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| 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 |
Low risk |
Quote: "All participants were included in the safety and ITT populations." |
| 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 |
