Anemia Study in Chronic Kidney Disease (CKD) : Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat -Forearm Blood Flow (ASCEND-FBF)

Study Overview
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Brief Summary
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Daprodustat has demonstrated an ability to effectively raise hemoglobin concentrations with lower erythropoietin (EPO) levels than those observed after administration of recombinant human erythropoietin (rhEPOs). Therefore, daprodustat has the potential to treat anemia of chronic kidney disease (CKD) with a lower cardiovascular (CV) risk than is observed with the rhEPOs. While the effect of rhEPOs on endothelial function has been assessed, to date the effect of daprodustat or other prolyl hydroxylase inhibitor (PHI) compounds on endothelial function has not. Therefore, the purpose of this study is to compare the effect of daprodustat to darbepoetin alfa on endothelial function by assessing FBF in participants with anemia of CKD by using venous occlusion plethysmography as a means to estimate the potential for daprodustat to have a lower risk of CV events as compared to rhEPO. This study will use a randomized, repeat dose, open label, parallel group design, in adult, not on-dialysis, male and female participants with anemia of CKD that are currently not treated with rhEPOs. The study will comprise of three study periods: a screening period starting up to 30 days prior to Day 1, a 42 day (6 week) treatment period, and a follow-up visit up to 14 days later. The total duration of participants involvement is up to 14 weeks (including screening and follow up visit). Approximately 50 participants will be randomized to either daprodustat or darbepoetin alfa.

Official Title
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A Randomized, Repeat Dose, Open Label, Parallel Group, Multi-center Study to Evaluate the Effect of Daprodustat Compared to Darbepoetin Alfa on Forearm Blood Flow in Participants With Anemia of Chronic Kidney Disease That Are Not Dialysis Dependent

Conditions
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Anaemia

Intervention / Treatment
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* Drug: Daprodustat
* Drug: Darbepoetin alfa
* Drug: Acetylcholine
* Drug: Sodium nitroprusside
* Drug: L-N-monomethyl arginine acetate (L-NMMA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be at least 18 years of age inclusive, at the time of signing the informed consent. Participants who are Stage 3, 4 or 5 CKD defined by estimated Glomerular Filtration Rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula. Hemoglobin as measured by HemoCue at screening visit and Day 1 is <=11.0 grams/deciliter (g/dL) [<=110 gram/Litre (g/L)]. Palpable brachial artery as assessed at screening. Participants, if necessary may be on stable maintenance oral iron supplementation (<50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period). If participants have been on intravenous (IV) iron, then participants will not have received IV iron for 4 weeks prior to the Day 1 visit. Male or female participants will be included. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who has been on an approved form of contraceptive for the 4 weeks prior to Day 1 and agrees to follow the contraceptive guidance until the Follow-up visit. Capable of giving signed informed consent. Exclusion Criteria: On dialysis or clinical evidence of impending need to initiate dialysis within 12 weeks of Day 1. Planned kidney transplant within 12 weeks of Day 1. Presence of an arteriovenous (AV) fistula. Recombinant human erythropoietin use within the 12 weeks prior to the screening visit and through Day 1. History of severe allergic or anaphylactic reactions or hypersensitivity to the study treatment or challenge agents, or excipients in the study treatments or challenge agents. Planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until all assessments on Day 42 have been successfully completed. The participant has participated in a clinical trial and has received an experimental investigational product within the prior 30 days or within 5 half-lives of the investigational product (whichever is longer) prior to screening and through Day 1. At or below the lower limit of the reference range at screening for Vitamin B12 (may rescreen in a minimum of 8 weeks). Ferritin <=50 nanograms/milliliter [<=50 microgram/liter (µg/L)] at screening. Transferrin saturation (TSAT) <=15% (0.15) at screening. Folate <2.0 nanogram/milliliter (4.5 nanomoles/liter; may rescreen in a minimum of 8 weeks) at screening. High sensitivity C-reactive protein (hs-CRP) >=50 micrograms/milliliter (>=50 mg/L) at screening. Myocardial infarction or acute coronary syndrome <=12 weeks prior to screening and through Day 1. Hospitalization for greater than 24 hours <=12 weeks prior to screening and through Day 1. Stroke or transient ischemic attack <=12 weeks prior to screening and through Day 1. Class 4 heart failure, as defined by the New York Heart Association (NYHA) functional classification system. Resting SBP >180 millimeters of mercury (mmHg) or DBP >110 mmHg at screening visit or current uncontrolled hypertension as determined by the investigator. QT interval corrected for heart rate using Bazett's formula (QTcB) >500 milliseconds (msec), or QTcB >530 msec in participants with bundle branch block. There is no corrected QT (QTc) exclusion for participants with a predominantly ventricular paced rhythm. Active chronic inflammatory disease that could impact erythropoiesis. History of bone marrow aplasia or pure red cell aplasia. Conditions, other than anemia of CKD, which can affect erythropoiesis. Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding from <=8 weeks prior to screening and through Day 1. ALT >2 times upper limit of normal (ULN; screening only). Bilirubin >1.5 times ULN (screening only); Isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35% Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Major surgery within the 12 weeks prior to screening and through Day 1, or planned during the study. Anticipated or planned vascular access surgery (i.e., arteriovenous [AV] fistula) within the 12 weeks prior to screening and through the Day 42 assessments. Received a tissue heart valve replacement or repair within the 6 months prior to screening or has received a mechanical heart valve replacement. Blood transfusion within 6 weeks prior to screening and through Day 1, or an anticipated need for blood transfusion during the study. Clinical evidence of an acute infection, or history of infection requiring IV antibiotic therapy from 8 weeks prior to screening and through Day 1. Prophylactic oral antibiotics are allowed. History of malignancy within the two years prior to screening and through Day 1 or currently receiving treatment for cancer, with the exception of localized squamous cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1. Platelet count <50,000/µL (<50 Giga cells per liter). History of a bleeding disorder (e.g., hemophilia). Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to either daprodustat or darbepoetin alfa. A central randomization approach will be used with stratification by center.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving Daprodustat<br>Participants will receive 2 milligram (mg) daprodustat tablets once daily via oral route for a period of 41 days. | Drug: Daprodustat<br>* Daprodustat will be available as 1 mg, 2 mg and 4 mg oral tablets. Daprodustat will be administered once daily by oral route without regard for food.<br>Drug: Acetylcholine<br>* Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.<br>Drug: Sodium nitroprusside<br>* Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.<br>Drug: L-N-monomethyl arginine acetate (L-NMMA)<br>* L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.<br>|
| Active Comparator: Participants receiving Darbepoetin alfa<br>Participants will receive Darbepoetin alfa solution for injection, administered as a single subcutaneous injection, once every two weeks (Days 1, 14 and 28). | Drug: Darbepoetin alfa<br>* Darbepoetin alfa will be given as solution for injection for subcutaneous administration every 2 weeks.<br>Drug: Acetylcholine<br>* Acetylcholine will be used as a challenge agent and will be infused at 7.5, 15 and 30 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.<br>Drug: Sodium nitroprusside<br>* Sodium nitroprusside will be used as a challenge agent and will be infused at 3 and 10 micrograms/minute each for 6 minutes per infusion into the brachial artery of the test arm.<br>Drug: L-N-monomethyl arginine acetate (L-NMMA)<br>* L-N-monomethyl arginine acetate will be used as a challenge agent and will be infused at a doses of 2 and 8 micromoles/minute for 6 minutes into the brachial artery of the test arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FBF Ratio in Response to Acetylcholine (Day 1 to Day 42) | Venous occlusion plethysmography was used for FBF assessment. Acetylcholine (ACH) was infused intra-arterially at 7.5, 15 and 30 micrograms/minute (ug/min) each for 6 minutes per infusion. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio. | Day 1 to Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Absolute FBF From Day 1 to Day 42 in Response to Acetylcholine | Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to acetylcholine is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine. | Day 1 to Day 42 | 
| Change in FBF Ratio in Response to Sodium Nitroprusside (Day 1 to Day 42) | Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio. | Day 1 to Day 42 | 
| Change in the Absolute FBF From Day 1 to Day 42 in Response to Sodium Nitroprusside | Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to sodium nitroprusside is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside. | Day 1 to Day 42 | 
| Change in FBF Ratio in Response to NG-monomethyl Arginine Acetate (L-NMMA) (Day 1 to Day 42) | Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 micromoles per minute (umol/min) each infused for 6 minutes into the brachial artery of the test arm. FBF ratio was defined as the ratio of a participant's treatment (infused) arm value divided by the non-treatment (non-infused) arm value. The overall ratio was determined by taking the participant's Day 42 FBF ratio and dividing by the Day 1 FBF ratio. | Day 1 to Day 42 | 
| Change in the Absolute FBF From Day 1 to Day 42 in Response to L-NMMA | Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF from Day 1 to Day 42 in response to L-NMMA is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA. | Day 1 to Day 42 | 
| Change in FBF Ratio in Response to Acetylcholine at Day 42 Versus (vs) Day 1 in Participants Treated With Daprodustat | Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio. | Day 1 and Day 42 | 
| Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat | Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio. | Day 1 and Day 42 | 
| Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat | Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio. | Day 1 and Day 42 | 
| Change in FBF Ratio in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa | Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio. | Day 1 and Day 42 | 
| Change in FBF Ratio in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa | Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio. | Day 1 and Day 42 | 
| Change in FBF Ratio in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa | Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. The Day 42 ratio was calculated by taking the participants Day 42 treatment (infused) arm and dividing by the Day 42 non-treatment (control) arm value. The Day 1 ratio was calculated by taking the participants Day 1 treatment (infused) arm and dividing by the Day 1 non-treatment (control) arm value. Change in FBF ratio from Day 1 to Day 42 was determined by taking the participants Day 42 ratio and dividing by the Day 1 ratio. | Day 1 and Day 42 | 
| Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Daprodustat | Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF in response to acetylcholine at Day 42 vs Day1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine in participants treated with daprodustat. | Day 1 and Day 42 | 
| Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Daprodustat | Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to sodium nitroprusside at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside in participants treated with daprodustat. | Day 1 and Day 42 | 
| Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Daprodustat | Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to L-NMMA at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA in participants treated with daprodustat. | Day 1 and Day 42 | 
| Change in the Absolute FBF in Response to Acetylcholine at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa | Venous occlusion plethysmography was used for FBF assessment. Acetylcholine was infused intra-arterially at 7.5, 15 and 30 ug/min each for 6 minutes per infusion. Measures were made in both arms concurrently. Change in the absolute FBF in response to acetylcholine at Day 42 vs Day1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to acetylcholine in participants treated with darbepoetin alfa. | Day 1 and Day 42 | 
| Change in the Absolute FBF in Response to Sodium Nitroprusside at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa | Venous occlusion plethysmography was used for FBF assessment. Sodium nitroprusside was infused at 3 and 10 ug/min each for 6 minutes per infusion into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to sodium nitroprusside at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to sodium nitroprusside in participants treated with darbepoetin alfa. | Day 1 and Day 42 | 
| Change in the Absolute FBF in Response to L-NMMA at Day 42 vs Day 1 in Participants Treated With Darbepoetin Alfa | Venous occlusion plethysmography was used for FBF assessment. Effects on basal nitric oxide synthesis was assessed using L-NMMA at doses of 2 and 8 umol/min each infused for 6 minutes into the brachial artery of the test arm. Measures were made in both arms concurrently. Change in the absolute FBF in response to L-NMMA at Day 42 vs Day 1 is the difference between absolute value of FBF in infused arm on Day 1 and Day 42 in response to L-NMMA in participants treated with darbepoetin alfa. | Day 1 and Day 42 | 
| Change in Augmentation Index (AIx) From Day 1 to 42 | Pulse wave analysis (PWA) is a reproducible, noninvasive method for assessing AIx (a measure of the contribution that wave reflection makes to the arterial pressure waveform). The amplitude and timing of the reflected wave ultimately depends on the stiffness of the small (pre-resistance) vessels and large arteries, and thus, AIx provides a measure of systemic arterial stiffness. A high-fidelity micro manometer was used to obtain accurate readings of the peripheral pressure waveforms by flattening, but not occluding, the radial artery of the dominant arm using gentle pressure. AIx was defined as the augmentation (difference between systolic peaks) expressed as a percentage of the overall pulse pressure. Data for change in AIx from Day 1 to 42 was presented. | Day 1 to Day 42 | 
| Change in Pulse Wave Velocity (PWV) From Day 1 to Day 42 | PWV was assessed with a high-fidelity micro manometer which was used to obtain accurate readings of the peripheral pressure waveforms by flattening, but not occluding, the carotid and femoral arteries as the two points of measure. Data for change in PWV from Day 1 to 42 was presented. | Day 1 to Day 42 | 
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical study participants, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/birth effect. | Up to 59 days | 
| Number of Participants With Any AE of Special Interest (AESI) | AESIs were identified based on non-clinical studies with daprodustat, clinical experience with recombinant human erythropoietins (rhEPOs), and current information regarding hypoxia-inducible factor (HIF)-regulated pathways in mediating hypoxia-associated pathophysiology. The AESIs for daprodustat were identified as follows: Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis; Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular access; Cardiomyopathy; Pulmonary artery hypertension; Cancer-related mortality and tumor progression and recurrence Esophageal and gastric erosions; Proliferative retinopathy, macular edema, choroidal neovascularization; Exacerbation of rheumatoid arthritis and Worsening of hypertension. | Up to 59 days | 
| Number of Participants Discontinuing the Randomized Study Treatment | Number of participants who discontinued the randomized study treatment were assessed. | Up to Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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darbepoetin alpha, challenge agents, daprodustat, FBF-CKD