Table 2.
Summary of Phase 3 randomised clinical trials evaluating efficacy of HIF-PHIs in the dialysis-dependent CKD population
| Trial (Author, year) | Countries | Design [population] | Comparator | N | Duration (weeks) | Primary efficacy endpoint | Primary outcome | Secondary anaemia-related outcomes | Iron parameters vs comparator |
|---|---|---|---|---|---|---|---|---|---|
| INCIDENT-HD | |||||||||
| Roxadustat | |||||||||
|
HIMALAYAS (Provenzano 2021) [46] |
US, Asia Europe, and South America, | Non-inferiority RCT (1:1) [ESA-naïve, 10.6 % in PD] | Epoetin-α | 1043 | 52 |
US-FDA endpoint: Δ Hb from BL to Weeks 28–52 EU-EMA endpoint: Hb>11 & Δ Hb 1–2 at Week 24 |
Δ Hb 2.57 vs 2.36 (p < 0.001 for superiority) 88.2% vs 84.4% |
↓ IV iron dose = transfusions (7.3 % vs 6.4%) |
= hepcidin ↓ ferritin = TSAT ↑ TIBC ↑ serum iron |
| Daprodustat | |||||||||
| ASCEND-ID (Singh 2022) [57] | Worldwide | Non-inferiority RCT (1:1) [ESA treated, 19.2 % in PD] | Darbepoetin-α | 312 | 52 | Δ Hb from BL to Weeks 28–52 | Δ Hb 1.02 vs 1.12 |
= IV iron dose = transfusion (12% vs 14%) = rescue therapy |
↓ hepcidin = Ferritin = TSAT ↑ TIBC ↑ serum iron |
| Vadadustat | |||||||||
| INNO2VATE (Eckardt 2021) [47] | Worldwide | Non-inferiority RCT (1:1) [ESA treated, 10.6 % in PD] | Darbepoetin-α | 369 | 116 | Δ Hb from BL to Weeks 24–36 | Δ Hb 1.26 vs 1.58 |
↓ Hb responders#: 44% vs 57% = transfusion (1.3% vs 1.8%) |
= hepcidin = Ferritin = TSAT |
| PREVALENT-HD | |||||||||
| Roxadustat | |||||||||
| SIERRAS (Charytan, 2021) [48] | US | Non-inferiority RCT (1:1) [ESA treated, 4.4 % in PD] | Epoetin-α | 741 | 52 | Δ Hb from BL to Weeks 28–52 | Δ Hb 0.39 vs − 0.09 |
= Hb responders*: 66% vs 59% ↓ IV iron dose ↓ transfusions (12.5% vs 21.1%) |
↓ hepcidin = Ferritin = TSAT ↑ TIBC ↑ serum iron |
| PYRENEES (Csilky 2021) [49] | Europe | Non-inferiority RCT (1:1) [ESA treated, 6.0 % in PD] | Epoetin-α (n = 258) or Darbepoetin (n = 163) | 838 | 104 |
Δ Hb from BL to Weeks 28–36 (no rescue therapy) Δ Hb from BL to Weeks 28–52 |
Δ Hb 0.43 vs 0.19 Δ Hb 0.36 vs 0.19 |
= Hb responders*: 84% vs 82% ↓ IV iron use and dose = transfusion (9.2% vs 12.9%) |
↓ hepcidin ↓ Ferritin = TSAT ↑ TIBC |
| ROCKIES (Fishbane 2022) [58] | Worldwide | Non-inferiority RCT (1:1) [ESA treated, 10.7 % in PD] | Epoetin-α | 2133 | 164 | Δ Hb from BL to Weeks 28–52 | Δ Hb 0.77 vs 0.68 |
↓ IV iron dose = transfusion (9.8% vs 13.2%) = rescue therapy = total time with Hb > 10 g/dL and 10–12 g/dL over Weeks 28–52 |
↓ hepcidin ↓ Ferritin = TSAT ↑ TIBC ↑ serum iron |
| Akizawa JASN 2020 [50] | Japan |
Non-inferiority RCT (1:1) [ESA treated] |
Darbepoetin | 301 | 24 | Δ Hb from BL to Weeks 18–24 | ΔHb − 0.04 vs − 0.03 |
= Achieved Hb target°: 79% vs 83% = IV iron use |
= hepcidin = ferritin = TSAT ↑ TIBC = serum iron |
|
FGCL‐4592‐806 (Chen 2019) [51] |
China | RCT (2:1) [ESA treated, 10.9 % in PD] | Epoetin-α | 304 | 27 | Δ Hb from BL to Weeks 23–27 | Δ Hb 0.7 vs 0.5 |
Δ Hb 0.9 vs 0.3 in high CRP patient ↓ oral iron use |
↓ hepcidin = Ferritin ↑ TSAT ↑ TIBC |
| Molidustat | |||||||||
| MIYABI HD-M (Akizawa 2021) [52] | Japan | Non-inferiority RCT (1:1) [ESA treated] | Darbepoetin-α | 229 | 52 | Δ Hb from BL to Weeks 32–36 | ΔHb − 0.14 vs − 0.07 |
↓ Achieved Hb target*: 73% vs 87% ↑ rescue therapy = transfusions = IV iron use and dose |
= hepcidin = ferritin = TSAT = TIBC = serum iron |
| Enarodustat | |||||||||
|
SYMPHONY HD (Akizawa 2021) [53] |
Japan | Non-inferiority RCT (1:1) [ESA treated] | Darbepoetin-α | 172 | 24 | Difference in mean Hb between arms at Weeks 20–24 | Mean: − 0.12 g/dL 95% CI: − 0.33 to 0.10 |
= Achieved Hb target*: 78% vs 88% = IV iron dose |
↓ hepcidin =ferritin ↑ TSAT ↑ TIBC ↑ serum iron |
| Daprodustat | |||||||||
| ASCEND-D (Singh 2021) [54] | Worldwide | Non-inferiority RCT (1:1) [ESA treated, 11.5 % in PD] | Epoetin-α (PD received darbepoetin)α | 2964 | 148 | Δ Hb from BL to Weeks 28–52 | Δ Hb 0.28 vs 0.10 |
= transfusion (15.7% vs 18.3%) = IV iron dose |
↓ hepcidin ↓ ferritin ↑ TIBC |
| NCT02969655 (Akizawa 2020) [53] | Japan | Non-inferiority RCT (1:1) [ESA treated] | Darbepoetin-α | 271 | 52 | Difference in mean Hb between arms at Weeks 40–52 | Mean: 0.1 g/dL 95% CI − 0.1 to 0.2 |
= Achieved Hb target°: 88% vs 90% ↓ IV iron use = oral iron use |
↓ hepcidin =ferritin ↑ TSAT ↑ TIBC ↑ serum iron |
| ASCEND-TD (Coyne 2022) [32] | Worldwide |
Non-inferiority RCT (2:1) [ESA treated] DA three times a week |
Epoetin-α | 407 | 52 |
Difference in mean Hb between arms at Weeks 40–52 Δ mean Hb from baseline |
Adjusted mean difference in Δ Hb from baseline − 0.05 g/dL (95% CI, − 0.21 to 0.10) | % Hb responders higher for daprodustat (80%) versus epoetin (64 %), p < 0.01 |
↓ hepcidin in the two groups = ferritin = TSAT ↑ TIBC ↑ serum iron |
| Desidustat | |||||||||
| DREAM-D (Ganz 2022) [59] | India | Non-inferiority RCT (1:1) [ESA-treated] | Epoetin-α | 392 | 24 | Δ Hb from baseline to Weeks 16–24 | Δ Hb 0.95 vs 0.80 |
↑ Hb responders¶: 59% vs 48% No patient received rescue therapy |
= hepcidin ↓ ferritin = TSAT |
| Vadadustat | |||||||||
| INNO2VATE (Eckardt 2021) [47] | Worldwide | Non-inferiority RCT (1:1) [ESA treated, 7.9 % in PD] | Darbepoetin-α | 3554 | 116 | Δ Hb from BL to Weeks 24–36 | Δ Hb 0.19 vs 0.36 |
↓ Hb responders #: 49 % vs 53% = transfusion (2.0% vs 1.3%) |
= hepcidin = Ferritin = TSAT |
| NCT03439137 (Nangaku 2021) [56] | Japan | Non-inferiority RCT (1:1) [ESA treated] | Darbepoetin-α | 323 | 52 | Difference in mean Hb between arms at Weeks 20–24 | Mean: − 0.05 g/dL 95% CI − 0.26 to 0.17 | = Achieved Hb target°: 75% vs 76% |
↓ hepcidin = ferritin = TSAT ↑ TIBC |
BL baseline, ESA erythropoiesis stimulating agents, EU-EMA European Union-European Medicine Agency, Hb haemoglobin, Δ Hb haemoglobin change, IV intravenous, NA not assessed [mixed] indicates enrolment of ESA-naïve and ESA-treated patients, rescue therapy included at least one among ESA transfusions IV iron, RCT randomised clinical trial, TIBC total iron binding capacity, TSAT transferrin saturation, US-FDA United States Food and Drug Administration
*Defined as Hb> 11 g/dL & Δ Hb > 1 g/dL or Hb > 11 g/dL & Δ Hb > 2 if baseline Hb < 8 g/dL; †defined as Hb > 10 & Δ Hb > 1 g/dL or Hb > 11 g/dL & Δ Hb > 2 if baseline Hb < 8 g/dL; °Hb target defined as 10–12 g/dL; §(1) the mean Hb level within the target range (11.0–13.0 g/dL) during the evaluation period (2) ≥ 50% of the Hb levels were in the target range during the evaluation period and (3) no rescue treatment,
#Defined as patients achieving country-specific target range at Weeks 24–36; *Defined as mean Hb ≥ 10.0 g/dL averaged over Weeks 28–52; °Hb target defined as 10–12 g/dL; ¶Defined as Hb 10–12 g/dL (at Weeks 16–24) & Δ Hb ≥ 1 g/dL by Week 24