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. 2022 Aug 25;2022(8):CD013751. doi: 10.1002/14651858.CD013751.pub2

INNO2VATE 2020a.

Study characteristics
Methods

  • Study design: parallel RCT (prevalent DD‐CKD trial)

  • Time frame: not reported

  • Duration of follow‐up: 52 weeks of treatment, form week 53 to end off treatment it was the long‐term treatment + 4 week follow‐up
Participants General information

  • Setting: multicentre (278 sites)

  • Country: international (Argentina, Australia, Brazil, Bulgaria, Canada, France, Germany, Israel, Italy, Korea, Mexico, Poland, Russian Federation, Serbia, Ukraine, UK; USA)

  • Inclusion criteria: ≥ 18 years; receiving chronic maintenance dialysis (either peritoneal or HD) for kidney failure for at least 12 weeks prior to screening; currently maintained on ESA therapy, with a dose received within 6 weeks prior to or during screening; mean screening Hb between 8.0 and 11.0 g/dL (USA) and between 9.0 and 12.0 g/dL (outside the USA)

  • Exclusion criteria: anaemia due to a cause other than CKD or subjects with active bleeding or recent blood loss; uncontrolled hypertension; severe heart failure at screening (NYHA class IV); 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; hypersensitivity to vadadustat, darbepoetin alfa, or any of their excipients

  • Target Hb

    • USA: 10 to 11 g/dL

    • non‐USA: 10 to 12 g/dL


Baseline characteristics

  • CKD stage: HD (3279); PD (272)

  • Number (randomised/analysed): treatment group (1777/1768); control group (1777/1769)

  • Mean age ± SD (years): treatment group (57.9 ± 13.9); control group (58.4 ± 13.8)

  • Sex (M, %): treatment group (990, 55.7%); control group (1004, 56.5%)

  • Time on dialysis: not reported

  • eGFR: not reported


Comorbidities

  • CV disease: treatment group (868/1777); control group (932/1777)

  • Heart disease: not reported

  • Hypertension: not reported

  • Diabetes: treatment group (971/1777); control group (998/1777)

  • Prior agents used (number, %)

    • Oral iron: not reported

    • IV iron: not reported
Interventions Treatment group (medium dose)*

  • Vadadustat (AKB‐6548) (oral): 150 to 450 mg//day, starting dose 300 mg, to a maximum of 600 mg/day


Control group

  • Darbepoetin alfa (Aranesp) (SC/I): titrated to achieve target Hb concentrations (USA: 10 to 11 g/dL; non‐USA: 10 to 12 g/dL)


Co‐interventions:

  • Not reported


*Note: dose was considered medium according to NDD‐CKD 2020
Outcomes Primary outcomes

  • Mean change in Hb between baseline and week 24 and 36

  • MACE from baseline visit to end of study (event‐driven, minimum 1 year)


Secondary outcomes

  • Mean change in Hb value between baseline and week 52

  • Proportion with Hb values within the target range during the primary evaluation period (week 36)

  • Adverse and serious adverse events to end of study (event‐driven, minimum 1 year)

  • Proportion of time with Hb values within the target range during the primary evaluation period (week 36)

  • Proportion of time with Hb values within the target range during the secondary evaluation period (week 52)

  • Proportion with Hb values within the target range during the secondary evaluation period (week 52)

  • Proportion with Hb increase of > 1.0 g/dL from baseline to end of study (event‐driven, minimum 36 weeks)

  • Time to achieve Hb increase of > 1.0 g/dL from baseline to end of study (event‐driven, minimum 36 weeks)

  • Mean change in Hb between baseline (mean pretreatment Hb) and the primary evaluation period (mean Hb from weeks 24 to 36 stratified by pre‐baseline ESA exposure (baseline visit, week 36)

  • Proportion receiving IV iron therapy by week 52

  • Mean monthly dose of IV elemental iron administered in subjects who have received IV iron (week 52)

  • Proportion receiving RBC transfusion(s) (week 52)
Notes

  • Funding: Akebia Therapeutics

  • Conflicts of interest: "K.U.E. has received fees from Akebia and Bayer and grants from Amgen, Bayer, Fresenius, Genzyme, Shire and Vifor. R.A. is a consultant for and on the scientific advisory board of Akebia; has received consulting fees from Bayer, Boehringer Ingelheim, Takeda, Daiichi Sankyo, Eli Lilly, Rlypsa, Reata, Opko, ZS Pharma and Merck; is on the data safety monitoring committee for AstraZeneca, Amgen (past) and Celgene (past) and attended advisory board meetings for AbbVie, Johnson & Johnson, Boehringer Ingelheim and Relypsa. A.G.J.: none. M.J.K. is a member of the Executive Steering Committee for Akebia; a consultant for FibroGen and is on the Data and Safety Management Committee for Micelle BioPharma. K.M. is a consultant for Akebia, Kyowa Kirin, Healthy.io and Fukuda Denshi and has received grants from Kyowa Kirin, Fukuda Denshi and the National Institutes of Health. P.A.M. is a consultant for Akebia. P.P. is on the Executive Steering Committee for Akebia. M.J.S. is a consultant for Cardurian and is on the Advisory Board for Bayer and the Steering Committee for Akebia. W.C.W. is on the Executive Steering Committee for Akebia and is a consultant for AstraZeneca, Bayer, Janssen, Merck, Relypsa and Vifor Fresenius Medical Care Renal Pharma. Y.M.K.F., Z.K., W.L., G.R. and D.V. are employees of Akebia. G.M.C. has received grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Amgen; personal fees from Akebia during the study; personal fees and other from Ardelyx; personal fees from AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Reata, Sanifit, Vertex, Satellite Healthcare, Angion, Bayer and ReCor and other fees from CloudCath, Durect and Outset"
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. It was not possible to assess if there was imbalance between intervention groups
Allocation concealment (selection bias) Unclear risk Method of allocation concealment was not reported in sufficient detail to permit judgement. It was not possible to assess if there was imbalance between intervention groups
Blinding of participants and personnel (performance bias)
All outcomes High risk Quote: "Open‐label study"
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 Unclear risk Ecardt 2021: cumulative data were reported for INNO2VATE 2020 and INNO2VATE 2020a: overall 3902/3923 participants were included into the analyses
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 Similar 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