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A Multicenter Randomized Controlled Study of the Efficacy and Safety of Daprodustat in Heart Failure Patients with Renal Anemia

HIF_PHi study (HIF_PHi study)

21

The baseline characteristics of the entire group were as follows: the mean age was 82.0 years, with 16 males (76.2%). 17 patients (81.0%) were classified as NYHA class II. The left ventricular ejection fraction (LVEF) was 53.6+-12.9%, hemoglobin (Hb) was 9.98+-0.60 g/dL, NT-ProBNP was 2895 pg/mL (IQR: 1015-4180), creatinine was 1.7 (IQR 1.2-2.5) mg/dL, and the estimated glomerular filtration rate (eGFR) was 31.8 (20.7-34.5) mL/min/1.73m2.

We randomized patients in a 1:1 ratio to either the daprodustat or control group by a web-based randomization system (Day 0). Randomization stratified according to baseline hemoglobin as an adjustment variable was applied to ensure balance groups for baseline hemoglobin. Regular visits were set at 2 weeks (Visit 1), 4 weeks (Visit 2), 8 weeks (Visit 3), 12 weeks (Visit 4), and 16 weeks (Visit 5). Participants randomized to the daprodustat group were given automatic dose adjustments based on a prespecified dose-adjustment algorithm. Of the 21 enrolled patients, 20 completed the follow-up period as stipulated in the protocol. One patient did not receive the protocol-specified treatment due to the occurrence of adverse events, leading to discontinuation of treatment.

During the follow-up period, one case each of femoral fracture, gastroenteritis, and diarrhea occurred. In all cases, a causal relationship with the medication was ruled out.

The primary endpoint, the difference in hemoglobin levels between the two groups after 16 weeks of randomization, was clearly significant (Mean hemoglobin levels after 16 weeks of randomization 12.1+-0.73 vs 10.3+-0.97, p < 0.001). No patient in the two groups received red blood cell transfusion during the present study follow up. Mean log NT-proBNP levels at 16 weeks were greater in daprostat group. On the other side, mean fe, transferrin saturation (TSAT), ferritin and hepcidin were less in HIF-PHi group than placebo group. There were no significant differences in transferrin, TIBC, total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol. The proportion of participants with an absolute increase of 5 points or more in KCCQ-TSS at 16 weeks compared to baseline showed no significant difference between the two groups (55.6% vs 44.4%, p = 0.99). Additionally, no significant differences were observed between the two groups in any parameters assessed by echocardiography or cardiac MRI.

In heart failure patients with renal anemia, daprodustat has been shown to effectively and safely improve hemoglobin levels. However, a post-hoc analysis of a large-scale clinical trial reported an increase in the total number of heart failure hospitalizations in non-dialysis chronic kidney disease patients treated with daprodustat compared to placebo. Based on these findings, an interim analysis was necessary in this study, and the trial was terminated before reaching the target number of cases.

Mar. 31, 2025

No

none

https://jrct.mhlw.go.jp/latest-detail/jRCT1051210196

Minamino Tohru

Juntendo University Hospital

3-1-3 Hongo Bunkyo-ku Tokyo

t.minamino@juntendo.ac.jp

Matsue Yuya

Juntendo University Hospital

3-1-3 Hongo Bunkyo-ku Tokyo

+81-3-3813-3111

y-matsue@juntendo.ac.jp

Complete

Mar. 18, 2022

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

Patients meet all of the following selection criteria and do not meet any of the exclusion criteria,will be eligible for the study.
1)Patients with heart failure who are 20 to 90 years old at the time of obtaining consent
2)eGFR<60mL/min/1.73m^2 at screening
3)Patients without atrial fibrillation at screening:BNP >100 pg/mL or NT-proBNP >600 pg/mL
Patients with atrial fibrillation at screening: BNP >150 pg/mL or NT-proBNP >900 pg/mL
4)Hemoglobin level >=7.5 g/dL and <11 g/dL at screening
5)Ferritin level>=100 ng/mL and TSAT>=20% at screening
6)Folic acid and vitamin B12levels must be above the lower limit of normal at screening.
7)Patients who have received sufficient explanations for participating in this study and have given their free written consent with full understanding.

1) NYHA class III/IV
2) On hemodialysis or peritoneal dialysis, or scheduled to be on hemodialysis in the next 6 months at informed concent
3) Treated with an ESA within 5 weeks prior to enrollment
4) Erythrocyte transfusion within 12 weeks prior to enrollment or expected to occur during the study period
5) Patients who have been treated with HIF-PH inhibitor
6) Patients with anemia other than chronic kidney disease and current or recent bleeding
7) History of sickle cell disease, myelodysplastic syndrome, myelofibrosis, hematologic tumor, myeloma, hemolytic anemia, thalassemia, or locus coeruleus
8) History of pulmonary hypertension, polycystic kidney disease
9) Malignancy noted within 2 years, except for treated basal cell carcinoma of the skin, squamous cell carcinoma cured by resection, or cervical intraepithelial carcinoma
10) History of acute myocardial infarction, cerebral infarction, deep vein thrombosis, or pulmonary thromboembolism within 48 weeks prior to enrollment
11) Others who are judged by the principal investigator to be inappropriate as research subjects

Both

Heart Failure with Renal Anemia

randomized controlled

[Pharmaceuticals] Derblock (generic name: daprodustat)
Dosage and administration method when untreated with erythropoiesis stimulating factor preparation
The usual starting dose for adults is 2 mg or 4 mg of daprodustat, which is orally administered once daily. After that, the dose may be adjusted according to the patient's condition, but the maximum dose should be up to 24 mg once a day.

Heart Failure with Renal Anemia

randomized controlled

D006333

Hemoglobin level at 16 weeks after randomization

The following items at 16 weeks after randomization
1) Presence or absence of red blood cell transfusion by 16 weeks after randomization
2) Presence or absence of score from 0 to 100 (KCCQ-TSS) calculated by the questionnaire on heart failure symptoms increased by 5 points or more compared to the baseline.
3) Blood tests :NT-proBNP, high-sensitivity troponin T, serum iron,transferrin,total iron binding capacity,transferrin saturation,ferritin,hepcidin,high-sensitivity C-reactive protein,total cholesterol,triglyceride,HDL cholesterol,LDL cholesterol,TNF-alpha,IL-1beta,IL-6, VEGF (plasma),angiopoietin
4) Echocardiography:left and right ventricular function analysis using M-mode,color Doppler,tissue Doppler,and strain analysis at the following cross sections Short-axis images (apex,papillary muscle level,mitral valve level), four-lumen,two-lumen,three-lumen images,right ventricle-focused four-lumen view of the apex (RV focused four chamber view)
5) Cardiac MRI:left and right heart function including strain analysis on cine MRI,native T1 abnormality and extracellular volume fraction on T1 mapping.

+81-3-3972-8111

Feb. 17, 2022

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