Table 1.
Summary of Phase 3 randomised clinical trials evaluating the efficacy of HIF-stabilizers in the non-dialysis CKD population
| Trial (Author, year) | Countries | Design [ESA exposure] | Comparator | N | Duration (weeks) | Primary efficacy endpoint | Primary outcome | Other anaemia-related outcomes | Iron parameters vs comparator |
|---|---|---|---|---|---|---|---|---|---|
| Roxadustat | |||||||||
| ANDES (Coyne 2020) [33] | USA, South America, Asia, Australia | RCT (2:1) [ESA-naïve] | Placebo | 922 | 52 |
US-FDA endpoint: Δ Hb from baseline to week 28–52 EU-EMA endpoint: Hb>11 & Δ Hb 1–2 at wk-24 |
Δ Hb 2.00 vs 0.16 86.0 % vs 6.6 % |
↓ rescue therapy ↓IV iron use: 2.5 % vs 4.9 % |
↓ hepcidin ↓ ferritin = TSAT ↑ TIBC ↑ serum iron |
| ALPS (Shutov 2021) [34] | Europe | RCT (2:1) [ESA-naïve] | Placebo | 594 | 52 |
US-FDA endpoint: Δ Hb from baseline to week 28–52 EU-EMA endpoint: Hb>11 & Δ Hb 1–2 at Week 24 |
Δ Hb 1.99 vs 0.30 79.2 % vs 9.9 % |
↓ rescue therapy) = IV iron use: 5 % vs 6 % |
↓ hepcidin ↓ ferritin ↓ TSAT |
| OLYMPUS (Fishbane 2021) [35] | Worldwide | RCT (1:1) [ESA-naïve] | Placebo | 2781 | 52 |
Δ Hb from baseline Weeks 28–52 |
Δ Hb 1.75 vs 0.4 |
↑ Hb response*: 77 % vs 9 % ↓ rescue therapy ↓IV iron use: 4 % vs 8 % |
↓ hepcidin ↓ ferritin = TSAT ↑ TIBC ↑ serum iron |
| FGCL-4592-808 (Chen 2019) [36] | China | RCT (2:1) [ESA-naïve] | Placebo | 154 | 9 | Δ Hb from baseline to Week 9 | Δ Hb 1.9 vs −0.4 |
↑ Hb response†: 75 % vs 0 % ↓ rescue therapy |
↓ hepcidin ↓ ferritin ↓ TSAT ↑ TIBC |
| DOLOMITIES (Barratt 2021) [37] | Europe | Non-inferiority RCT (1:1) [ESA-naïve] | Darbepoetin-α | 616 | 104 | Hb>11 & Δ Hb 1–2 | 89.5 % vs 78 % |
↓ IV iron use: 6 % vs 13 % ↓ IV iron dose ↓ oral iron use |
= ferritin = TSAT = serum iron |
| (Akizawa 2021) [38] | Japan | Non-inferiority RCT (1:1) [ESA-treated] | Darbepoetin-α | 334 | 52 | Δ Hb from baseline to Weeks 18–24 | Δ Hb 0.15 vs 0.22 |
= Achieved Hb target °: 70 % vs 76 % Iron therapy: NA |
= hepcidin = ferritin = TSAT = TIBC = serum iron |
| Molidustat | |||||||||
| MIYABI ND-M (Yamamoto 2021) [39] | Japan | Non-inferiority RCT (1:1) [ESA-treated] | Darbepoetin-α | 164 | 52 | Δ Hb from baseline to Weeks 30–36 | Δ Hb 0.36 vs 0.24 |
= Hb responders§ 72 % vs 77 % = IV iron use: 2 % vs 2 % ↑ oral iron use: 56 % vs 39 % ↓ iron dose |
↓ hepcidin ↓ ferritin ↓ TSAT |
| MIYABI ND-C (Yamamoto 2021) [40] | Japan | Non-inferiority RCT (1:1) [ESA-naïve] | Darbepoetin-α | 162 | 52 | Δ Hb from baseline to Weeks 30–36 | Δ Hb 1.32 vs 1.69 |
↓ Hb responders§ : 60 % vs 83 % = IV iron use: 5 % vs 5 % ↑ oral iron use: 50 % vs 41 % ↓ iron dose |
↓ hepcidin |
| Daprodustat | |||||||||
| ASCEND-ND (Singh 2021) [41] | Worldwide | Non-inferiority RCT (1:1) [Mixed] | Darbepoetin-α | 3872 | 148 | Δ Hb from baseline to Weeks 28–52 | Δ Hb 0.74 vs 0.66 |
↓ rescue therapy = transfusions: 13 % vs 14 % = IV iron use: 14 % vs 13 % |
↓ hepcidin = ferritin ↓ TSAT ↑ TIBC = serum iron |
| Desidustat | |||||||||
| DREAM-ND (Agrawal 2022) [45] | India, Sri Lanka | Non-inferiority RCT (1:1) [ESA-naïve] | Darbepoetin-α | 588 | 24 | Δ Hb from baseline to Weeks 16–24 | Δ Hb 1.95 vs 1.83 |
↑ Hb responders¶: 78 % vs 68 % No patient received rescue therapy |
↓ hepcidin = ferritin = TSAT = serum iron |
| Enarodustat | |||||||||
| SYMPHONY ND (Akizawa 2021) [42] | Japan | Non-inferiority RCT (1:1) [Mixed] | Darbepoetin-α | 216 | 24 | Difference in mean Hb level between arms at Weeks 20–24 | Mean: 0.09 g/dL 95 % CI: −0.07–0.26 |
= Achieved Hb target °: (ESA-naïve: 71 % vs 85 %) ESA-treated 79 % vs 77 %) = oral iron use: 40 % vs 41 % |
↓ hepcidin ↓ Ferritin ↓ TSAT ↑ TIBC |
| Vadadustat | |||||||||
| MT-6548-J01 (Nangaku 2021) [43] | Japan | Non-inferiority RCT (1:1) [Mixed] | Darbepoetin-α | 304 | 52 | Mean Hb at Week 20–24 | Hb 11.66 vs 11.93 |
= Achieved Hb target ‡: 89 % vs 88 % = oral iron use: 34 % vs 29 % = oral iron dose |
↓ hepcidin ↓ ferritin ↓ TSAT ↑ TIBC |
| PRO2TECT (Chertow 2021) [44] | Worldwide | Non-inferiority RCT (1:1) [Mixed] | Darbepoetin-α | 3471 | 168 | Δ Hb from baseline to Week 24–36 |
Δ Hb 1.52 vs 1.48 (in ESA-naïve) Δ Hb 0.41 vs 0.42 (in ESA-treated) |
= Hb responders# (ESA-naïve: 50 % vs 50 %; ESA-treated: 60 % vs 61 %) ↓ rescue therapy Iron therapy: NA |
|
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; ‡Hb target defined as 11–13 g/dL, #Defined as patients achieving country-specific target range at Weeks 24–36; ¶Defined as Hb 10–12 g/dL (at Weeks 16–24) & Δ Hb ≥ 1 g/dL by Week 24