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

Akizawa 2017.

Study characteristics
Methods

  • Study design: parallel RCT

  • Time frame: November 2013 to August 2014

  • Duration of follow‐up: 8 weeks (treatment phase 4 weeks + 4 weeks follow‐up)
Participants General information

  • Setting: multicentre (21 sites)

  • Country: Japan

  • Inclusion criteria: CKD with an eGFR ≤ 89 mL/min/1.73 m² not requiring dialysis for 3 months since study completion; mean of two Hb values at screening and Hb test (at least 1 week apart from the screening test) < 10.0 g/dL, with a difference of ≤ 1.0 g/dL between the two values; TSAT ≥ 5% and ferritin ≥ 30 ng/mL at screening; serum folate ≥ 4.0 ng/mL; vitamin B12 ≥ 180 pg/mL at screening

  • Exclusion criteria: proliferative retinopathy, age‐related macular degeneration, retinal vein occlusion and/or macular oedema that is considered to require treatment; Immunological disease with severe inflammation as assessed by the Investigator; even if the inflammation is in remission (e.g. SLE, rheumatoid arthritis, Sjogren's syndrome, coeliac disease); history of gastric/intestinal resection considered influential on the absorption of the drug in the GI tract or evidence of active gastroparesis; uncontrollable hypertension (more than one third DBP > 100 mm Hg within 16 weeks prior to screening); congestive HF (NYHA classification III or higher); history of hospitalisation for stroke, MI or lung infarction within 24 weeks before screening; positive for anti‐HCV Ab, HBsAg or HIV; anaemia other than anaemia due to low/absent renal production of EPO (e.g. iron deficiency anaemia, haemolytic anaemia, pancytopenia); using ESA, anabolic androgenic steroid, testosterone enanthate or mepitiostane within 6 weeks before screening

  • Target Hb: increase of at least 0.5 g/dL, 1.0 g/dL, 1.5 g/dL, and 2.0 g/dL


Baseline characteristics

  • CKD stage: HD

  • Number (randomised/analysed): treatment group 1 (19/19); treatment group 2 (20/20); treatment group 3 (19/19); treatment group 4 (20/20); control group (19/18)

    • ITT, while participants assessed in the safety population analysis were: treatment group 1 (19/19); treatment group 2 (20/20); treatment group 3 (19/19); treatment group 4 (20/20); control group (19/19)

  • Mean age ± SD (years): treatment group 1 (61.6 ± 8.49); treatment group 2 (58.9 ± 9.90); treatment group 3 (66.0 ± 9.23); treatment group 4 (62.2 ± 11.13); control group (63.4 ± 8.98)

  • Sex (M, %): treatment group 1 (8, 42%); treatment group 2 (12, 60%); treatment group 3 (7, 37%); treatment group 4 (11, 55%); control group (12, 63%)

  • Time on dialysis: not reported

  • eGFR: not reported


Comorbidities

  • CV disease: not reported

  • Heart disease: not reported

  • Hypertension: not reported

  • Diabetes (number, %): treatment group 1 (9, 47%); treatment group 2 (5, 25%); treatment group 3 (2, 11%); treatment group 4 (9, 45%); control group (6, 19%)

  • Prior agents used (number, %): all participants took ESA before randomisation

    • Oral iron: treatment group 1 (2, 11%); treatment group 2 (1, 5%); treatment group 3 (1, 5%); treatment group 4 (1, 5%); control group (0, 0%)

    • IV iron: treatment group 1 (1, 5%); treatment group 2 (4, 20%); treatment group 3 (7, 37%); treatment group 4 (2, 10%); control group (5, 26%)
Interventions Treatment group 1 (low‐dose)*

  • Daprodustat (GSK1278863) (oral): 4 mg once/day for 4 weeks


Treatment group 2 (medium‐dose)

  • Daprodustat (GSK1278863) (oral): 6 mg once/day for 4 weeks


Treatment group 3 (medium dose)

  • Daprodustat (GSK1278863) (oral): 8 mg once/day for 4 weeks


Treatment group 4 (high‐dose)

  • Daprodustat (GSK1278863) (oral): 10 mg once/day for 4 weeks


Control group

  • Placebo (oral): once/day


Co‐interventions

  • Subjects could be receiving stable maintenance oral or IV iron supplementation (IV iron ≤ 100 mg/week); however, changing the iron regimen during the study was not permitted


*Note: If data were not available to report HIF considering the dose (low, medium and high dose), the analyses have been performed considering the average dose > dose assessed according to Meadowcroft 2019
Outcomes Primary outcome

  • Hb CFB* at week 4 criteria. Hb levels were measured at screening, day 1, each week during the study, early withdrawal, and follow‐up (week 8)


Secondary outcomes

  • Hb response at week 4

  • Percentage who achieved Hb response at week 4

  • Number who reached pre‐defined Hb stopping criteria up to week 4

  • Maximum observed CFB EPO up to week 4

  • Maximum observed percent CFB in peak VEGF up to week 4

  • Percent CFB in hepcidin up to week 4

  • CFB in ferritin at week 4

  • CFB in TIBC, UIBC and iron at week 4

  • CFB in transferrin at week 4

  • Percent CFB in TSAT at week 4

  • Plasma pharmacokinetic concentration of GSK1278863 and metabolites at week 4

  • Adverse events and serious adverse events on therapy

  • Chemistry and haematology data of potential clinical importance up to week 4

  • SBP and DBP of potential clinical importance up to week 4

  • Heart rate of potential clinical importance up to week 4

  • Abnormal ECG findings up to week 4


*CFB was calculated by subtracting the baseline value from the post‐dose value at week 4
Notes

  • Funding: GlaxoSmithKline

  • Conflicts of interest: "Y.E., T.K., N.K., and K.H. are employees of GSK, and H.N., J.L., and A.C. are employees of GSK and are GSK shareholders. Y.I. is a former GSK employee. T.A., Y.T., and M.N. (all external physicians) received a consultant fee from GSK as medical advisors" 
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. 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."
Although author reported that the study used a double‐blind design, information about blinding of participants and investigators were not clearly stated. 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. Reporting of some outcomes (adverse effects) were unlikely to be biased because outcome assessors were blinded to treatment assignment
Incomplete outcome data (attrition bias)
All outcomes Unclear risk Quote: "A total of 97 subjects were randomized, of whom 86 (89%) subjects completed the study. Across treatment groups, the predominant reasons for premature withdrawal were reaching protocol‐defined stopping criteria and AEs."
ITT: treatment group 1 (19/19); treatment group 2 (20/20); treatment group 3 (19/19); treatment group 4 (20/20); control group (19/18)
Safety population: treatment group 1 (19/19); treatment group 2 (20/20); treatment group 3 (19/19); treatment group 4 (20/20); control group (19/19)
Selective reporting (reporting bias) High risk All of the planned outcomes on ClincialTrials.gov were not 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
Funder was likely to influence data analysis and study reporting or interpretation
Authors declared conflicts of interest