A Study to Evaluate Safety and Efficacy of GSK1278863 in Non-Dialysis Dependent (NDD) Subjects With Anemia Associated With Chronic Kidney Diseases (CKD)

Study Overview
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Brief Summary
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This study will be conducted in approximately 228 subjects with anemia associated with CKD who are not on dialysis. Two groups of subjects will be enrolled into the study: Group 1: recombinant human erythropoietin (rhEPO) naive subjects; Group 2: rhEPO users, who are currently receiving rhEPO. Subjects who are rhEPO naive will be randomized to receive either GSK1278863 once daily (QD) or rhEPO in a 3:1 fashion; subjects who are receiving an rhEPO before enrolling (rhEPO users) will be randomized in a 1:1 fashion to GSK1278863 QD or to the control arm. For those randomized to the control arm, the decision around whether the subject requires rhEPO, the selection of the type of rhEPO (if needed) and the choice of rhEPO dose to achieve and maintain Hgb concentrations within the target range should be based on Investigator clinical judgment, with the historical rhEPO dose and the current Hgb value being considered. The study consists of a screening phase of at least 4 weeks, a 24-week treatment phase and a follow-up visit that will occur approximately 4 weeks after completing treatment. It is anticipated that the data generated will enable selection of the starting dose(s) and optimize dose adjustment regimen(s) for Phase 3 clinical trials.

Official Title
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A 24-week, Phase IIB, Randomized, Controlled, Parallel Group, Multi-center Study to Evaluate the Safety and Efficacy of GSK1278863 in Subjects With Anemia Associated With Chronic Kidney Diseases Who Are Not on Dialysis.

Conditions
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Anaemia

Intervention / Treatment
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* Drug: GSK1278863
* Drug: rhEPO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: >=18 years of age. (Week -4 verification only) Gender: Female and male subjects. (Week -4 verification only) Females: If of childbearing potential, must agree to use one of the approved contraception methods, from Screening until completion of the Follow-up Visit OR Of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy, or oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the approved contraception methods if they wish to continue their HRT during the study. Otherwise they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Corrected QT interval (QTc): Bazett's Correction of QT Interval (QTcB) <470 milliseconds (msec) or QTcB <480 msec in subjects with bundle branch block. There is no QTc criterion for subjects with a predominantly paced rhythm. CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 defined by electronic estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula. Hgb: Group 1 (rhEPO naïve): Baseline Hgb of 8.0-11.0 g/dL (inclusive) (USA sites only: 8.0-10.0 g/dL, inclusive); Group 2 (rhEPO users): Baseline Hgb of 9.0-11.5 g/dL (inclusive) (USA sites only: 9.0-10.5, inclusive). Stable rhEPO dose for rhEPO users: Group 2 subjects must be using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses that varied by no more than 50% during the 4 weeks prior to Week -4. At Day 1 (randomization), confirm that total weekly doses varied by no more than 50% during the screening period. Oral iron therapy: If on oral iron, then doses must not be changed for the 4 weeks prior to Week -4, during the screening phase, and through the first 4 weeks after Randomization. Exclusion Criteria: Dialysis: On dialysis or planning to initiate dialysis during the study. Renal transplant: Pre-emptive or scheduled renal transplant. High rhEPO dose: An epoetin dose of >=360 IU/kg/week intravenous (IV) or >=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of >=1.8 microgram per kilogram per week (mcg/kg/week) IV or SC within the prior 8 weeks through Day 1 (randomization). Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Day 1 (randomization). IV iron therapy: Use of IV iron for 4 weeks prior to Screening Week -4, during the screening phase, and through the first 4 weeks after Randomization Vitamin B12: Below the lower limit of the reference range (may rescreen in a minimum of 8 weeks). Folate: <2.0 nanogram per millilitre (ng/mL) (<4.5 nanomoles per liter [nmol/L]) (may rescreen in a minimum of 4 weeks). Ferritin: <40 ng/mL (<40 mcg/L). Transferrin saturation (TSAT): Below the lower limit of the reference range Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening through Day 1 (randomization). Stroke or transient ischemic attack: Within the 8 weeks prior to Week -4 Screening through Day 1 (randomization). Heart failure: Class III/IV heart failure as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Week -4 Screening through Day 1 (randomization), symptomatic right heart failure diagnosed prior to Week -4 Screening through Day 1 (randomization). Uncontrolled hypertension: Defined as diastolic blood pressure (DBP) >100 mmHg or systolic blood pressure (SBP) >170 mmHg at Week -4 and reconfirmed at Day 1. Thrombotic Disease: History of thrombotic disease (e.g., venous thrombosis such as deep vein thrombosis or pulmonary embolism, or arterial thrombosis such as new onset or worsening limb ischemia requiring intervention), except vascular access thrombosis within the 8 weeks prior to Week -4 Screening through Day 1 (randomization). Ophthalmology disease: Meeting any ophthalmologic-related exclusion criteria determined at the Screening ophthalmology exam. Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Week -4 Screening through Day 1 (randomization). Hematological disease: Any hematological disease including those affecting platelets, white or red blood cells (e.g. sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia and thalassemia), coagulation disorders (e.g., antiphospholipid syndrome, Protein C or S deficiency), or any other cause of anemia other than renal disease diagnosed prior to Week -4 Screening through Day 1 (randomization). Liver disease: Current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or evidence at Screening of abnormal liver function tests [alanine transaminase (ALT) or aspartate transaminase (AST) >2.0 x upper limit of normal (ULN) or total bilirubin >1.5 x ULN]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study. Major surgery: Major surgery (excluding vascular access surgery) within the prior 8 weeks, during the Week -4 Screening phase or planned during the study. Transfusion: Blood transfusion within the prior 8 weeks, during the Week -4 Screening phase or an anticipated need for blood transfusion during the study. Gastrointestinal (GI) Bleeding: Evidence of actively bleeding peptic, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks prior to Week -4 Screening through Day 1 (randomization). Acute infection: Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Week -4 Screening through Day 1 (randomization). Malignancy: Subjects with a history of malignancy within the prior 5 years, who receiving treatment for cancer, or who have a strong family history of cancer (e.g., familial cancer disorders); with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to Week -4 Screening through Day 1 (randomization). Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (see GSK1278863 IB for list of excipients and rhEPO (refer to local product labelling for details). Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Week -4 Screening until the Follow-up Visit. Prior investigational product exposure: The Subject has participated in a clinical trial and has received an experimental investigational product within the prior 30 days from Week -4 Screening through Day 1 (randomization). Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk. Patient participation: Unwillingness or inability of the subject to follow the procedures or lifestyle or dietary restrictions outlined in the protocol. Pregnancy or Lactation: Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test OR women who are lactating at Week -4 Screening or during the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1278863<br>Subjects will be administered GSK1278863 QD. Starting dose will be based on data from previous studies with GSK1278863 and dose-response modelling, as well as Baseline Hgb concentration. After 4 Week of fixed dose period, dose may be adjusted to achieve Hgb 9.0 to 10.5 g/dL | Drug: GSK1278863<br>* Film-coated tablets containing 0.5 mg, 1 mg, 2 mg, 5mg or matching placebo<br>|
| Other: Control<br>All subjects who are randomized to the Control arm will receive rhEPO (epoetins or their biosimilars, or darbepoetin) as necessary per standard of care, to maintain Hgb levels within the target range. The decision around whether a subject requires rhEPO, selection of the type of rhEPO and rhEPO dose should be based on Investigator clinical judgment, with the historical rhEPO dose (where applicable) and the current Hgb value being considered. | Drug: rhEPO<br>* Locally sourced rhEPO. All subjects who are randomized to the Control arm will receive rhEPO (epoetins or their biosimilars, or darbepoetin) as necessary per standard of care, to maintain Hgb levels within the target range. The decision around whether a subject requires rhEPO, selection of the type of rhEPO and rhEPO dose should be based on Investigator clinical judgment, with the historical rhEPO dose (where applicable) and the current Hgb value being considered..<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Hemoglobin (Hgb) Concentration at Week 24 | The original Hgb Criteria for Group 1- rhEPO naive participants with a stable baseline Hgb of 8.0-10.0 g/dL (8.0-10.0 g/dL USA site only) and for Group 2- rhEPO users with a stable baseline Hgb of 9.0-10.5 g/dL (9.0-10.5 g/dL USA site only); the Hgb target range was 9.0 to 10.5 g/dL (9.0-10.5 g/dL USA site only). The study amended Hgb Criteria for Group 1- rhEPO naive participants with a stable baseline Hgb of 8.0-11.0 g/dL and Group 2- rhEPO users with a stable baseline Hgb of 9.0-11.5 g/dL; Hgb target range - 10.0 to 11.5 g/dL. Data are presented for those participants following the original criteria (Original) and those following the amended (Amended) criteria. The primary objective was to characterize the ability of GSK1278863 to achieve mean Hgb response within the target range. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hemoglobin (Hgb) in the Target Range at Week 24 | Target range is defined as: Original Hgb Criteria of 9.0 to 10.5 gram/deciliter (g/dL), and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. | Week 24 | 
| Number of Participants Reaching Pre-defined Hgb Stopping Criteria | The Hgb stopping criteria was a value of <7.5 mg/dL obtained on-site via a validated point-of-care Hgb measurement device, which necessitated permanent discontinuation of the study medication. None of the participants met the stopping criteria therefore there is no data to present for this outcome measure. | Over a period of 24 Weeks | 
| Percent Change From Baseline in Hepcidin Concentration at Week 24 | Baseline is the last pre-dose hepcidin value. Percent change was calculated as 100 multiplied by (exponential of mean change on log scale minus 1). Change was calculated by subtracting the Baseline value from the Week 24 value. | Baseline and Week 24 | 
| Maximum Observed Change From Baseline in Serum Erythropoietin (EPO) | Blood samples for control arm were collected pre-dose for EPO measurement. Blood samples for GSK1278863 arms were collected on Day 1 (pre-dose ), Week 4 (6-12 hours post-dose ), Week 4 (7-13, 8-14, 9-15, hours post-dose ), Week 8 (pre -dose ), Week 12 (pre -dose ), Week 16 (pre -dose ), Week 20 (pre -dose , 3 hour post-dose ) Week 24 (pre -dose ), and Week 28 (pre -dose ) for EPO measurement. The maximum observed change from baseline in EPO was recorded for each arm. Baseline value for EPO is the pre-dose value on Day 1. Change from Baseline in EPO was calculated as the individual post-baseline values minus the Baseline value. | Baseline to Week 24 | 
| Maximum Observed Percent Change From Baseline in Vascular Endothelial Growth Factor (VEGF) | Blood samples for control arm were collected pre-dose for VEGF measurement. Blood samples for GSK1278863 arms were collected on Day 1 (pre-dose ), Week 4 (6-12 hours post-dose ), Week 4 (7-13, 8-14, 9-15, hours post-dose ), Week 8 (pre -dose ), Week 12 (pre -dose ), Week 16 (pre -dose ), Week 20 (pre -dose , 3 hour post-dose ) Week 24 (pre -dose ), and Week 28 (pre -dose ) for VEGF measurement. The maximum observed change from baseline in VEGF was recorded for each arm . Baseline value for VEGF is the pre-dose value on Day 1. Change from Baseline in VEGF was calculated as the individual post-baseline values minus the Baseline value. | Baseline and up to Week 24 | 
| Percentage of Time Within, Below, and Above Hemoglobin (Hgb) Target Range, Between Weeks 12 and 24 | The number of days a participant's Hgb was within target range was calculated by estimating (using linear interpolation) the number of days within target range between two scheduled Hgb visits. Percentage of time within range for a participant was calculated by dividing the total number of days that Hgb was within range during Weeks 12 to 24 by the total number of days the participant remained on treatment during Weeks 12 to 24. Similary, percent of time above and below Hgb target range was calculated. Target range was defined as: Original Hgb Criteria of 9.0 to 10.5 g/dL, and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. | Weeks 12 to 24 | 
| Change From Baseline in Ferritin Concentration at Week 24 | Baseline is the last pre-dose ferritin value. Change was calculated by subtracting the Baseline value from the Week 24 value. | Baseline and Week 24 | 
| Change From Baseline in Transferrin Concentration at Week 24 | Baseline is the last pre-dose transferrin value. Change from Baseline in transferrin was calculated by subtracting the Baseline value from the Week 24 value. | Baseline and Week 24 | 
| Percent Change From Baseline in Transferrin Saturation at Week 24 | Transferrin saturation is measured as a percentage; it is a ratio of serum iron and total iron-binding capacity. Baseline is the last pre-dose transferrin saturation value. Percent change was calculated as 100 multiplied by (exponential of mean change on log scale minus 1). Change was calculated by subtracting the Baseline value from the post-dose value. | Baseline and Week 24 | 
| Change From Baseline in Total Iron at Week 24 | Baseline is the last pre-dose total iron value. Change from Baseline was calculated by subtracting the Baseline value from the Week 24 value. | Baseline and Week 24 | 
| Change From Baseline in Total Iron Binding Capacity (TIBC) at Week 24 | TIBC measures the blood's capacity to bind iron with transferrin. Baseline is the last pre-dose TIBC value. Change from Baseline in TIBC was calculated by subtracting the Baseline value from the Week 24 value. | Baseline and Week 24 | 
| Change From Baseline in Reticulocyte Hemoglobin (CHr) at Week 24 | Reticulocytes are slightly immature red blood cells. Reticulocyte Hgb content is used to differentiate iron deficiency from other causes of anemia. Baseline is the last pre-dose CHr value. Change from Baseline in reticulocyte Hgb was calculated by subtracting the Baseline value from the post-dose value. | Baseline and Week 24 | 
| Change From Baseline in Hematocrit at Week 24 | Baseline is the last pre-dose hematocrit value. Change from Baseline was calculated by subtracting the Baseline value from the Week 24 value. | Baseline and Week 24 | 
| Change From Baseline in Red Blood Cell Count at Week 24 | Baseline is the last pre-dose red blood cell count. Change from Baseline in red blood cell count was calculated by subtracting the Baseline count from the post-dose count. | Baseline and Week 24 | 
| Change From Baseline in Reticulocyte Cell Count at Week 24 | Reticulocyte count is a blood test that measures the percentage of reticulocytes in the blood. Reticulocytes are slightly immature red blood cells. Baseline is the last pre-dose red reticulocyte count. Change from Baseline in reticulocyte cell count was calculated by subtracting the Baseline count from the Week 24 count. | Baseline and Week 24 | 
| Concentration of GSK1278863 and Relevant Metabolites as a Population Pharmacokinetic Endpoint | Blood samples were collected for individual plasma GSK1278863 and metabolite (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531401, and GSK2531403) concentration measurement on Day 1 (pre-dose), Wk 4 (6-12 hour, 7-13 hour, 8-14 hour, 9-15 hour post-dose), and Wk 20 (pre-dose, 1 hour, 2 hour, 3 hour post-dose). Participants available in each arm at the specified time points have been presented. | Day 1 (pre-dose), Week (Wk) 4 (6-12 hour, 7-13 hour, 8-14 hour, 9-15 hour post-dose), and Wk 20 (pre-dose, 1 hour, 2 hour, 3 hour post-dose) | 
| Mean Number of Dose Adjustments up to 24 Weeks | After 4 Weeks, the need to adjust the dose of GSK1278863 was evaluated at every scheduled visit, to maintain hemoglobin within the target range. Target range was defined as: Original Hgb Criteria of 9.0 to 10.5 g/dL, and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. Dose adjustments were assigned automatically via the interactive voice/web response system. | From Week 4 up to 24 Weeks | 
| Number of Participants With Dose Adjustments up to 24 Weeks, as a Measure of Dose Adjustment Frequency | After 4 Weeks, the need to adjust the dose of GSK1278863 was evaluated at every scheduled visit, to maintain hemoglobin within the target range. Target range was defined as: Original Hgb Criteria of 9.0 to 10.5 g/dL, and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. Dose adjustments were assigned automatically via the interactive voice/web response system. Frequency is presented as the number of participants with dose adjustment(s) once, twice, thrice, four times, or five times. | From week 4 up to 24 weeks | 
| Timing of Dose Adjustments at Weeks 4, 8, 12, 16, and 20 | After 4 Weeks, the need to adjust the dose of GSK1278863 was evaluated at every scheduled visit, to maintain hemoglobin within the target range. Target range was defined as: Original Hgb Criteria of 9.0 to 10.5 g/dL, and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. Dose adjustments were assigned automatically via the interactive voice/web response system. The number of participants with an adjustment are presented at the timings at which adjustments were done. | From Week 4 up to Week 20 | 
| Mean Total Cumulative Dose of GSK1278863 up to 24 Weeks | The starting dose was kept constant for the first 4 Weeks after randomization. Later, the need to adjust the dose of GSK1288863 was evaluated at every scheduled visit according to a pre-specified algorithm, to achieve and maintain hemoglobin within the specified target range. Target range was defined as: Original Hgb Criteria of 9.0 to 10.5 g/dL, and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. | Up to 24 Weeks | 
| Mean Final Dose of GSK1278863 up to 24 Weeks | The starting dose was kept constant for the first 4 Weeks after randomization. Later, the need to adjust the dose of GSK1288863 was evaluated at every scheduled visit according to a pre-specified algorithm, to achieve and maintain hemoglobin within the specified target range. Target range was defined as: Original Hgb Criteria of 9.0 to 10.5 g/dL, and Amended Hgb Criteria of 10.0 to 11.5 g/dL. Sites in the USA used 9.0 to 10.5 g/dL. | Up to 24 Weeks | 
| Number of Hemoglobin (Hgb) Excursions | A Hgb excursion is a series of decreasing or increasing Hgb values differing by >=1.5 grams per deciliter. Hgb cycle is calculated as two consecutive Hgb excursions in different directions. | Up to 24 Weeks. | 
| Number of Hemoglobin (Hgb) Cycles up to 24 Weeks | A Hgb cycle is calculated as two consecutive Hgb excursions in different directions. A Hgb excursion is a series of decreasing or increasing Hgb values differing by >=1.5 grams per deciliter. | Up to 24 Weeks | 
| Number of Dose Cycles up to 24 Weeks | A dose cycle is a series of three directional dose changes (that is, increase, decrease, increase; or decrease, increase, decrease). | Up to 24 weeks | 
| Number of Participants With at Least One Hemoglobin (Hgb) Excursion up to 24 Weeks. | A Hgb excursion is a series of decreasing or increasing Hgb values differing by >=1.5 grams per deciliter. | Up to 24 weeks | 
| Number of Participants With at Least One Hemoglobin (Hgb) Cycle up to 24 Weeks | A Hgb excursion is a series of decreasing or increasing Hgb values differing by >=1.5 grams per deciliter. A Hgb cycle is two consecutive Hgb excursions in different directions. | Up to 24 weeks | 
| Number of Participants With at Least One Dose Cycle up to 24 Weeks | A dose cycle is a series of three directional dose changes (that is, increase, decrease, increase; or decrease, increase, decrease). participants | Up to 24 weeks | 
| Number of Participants Receiving Additional Therapies of Blood Transfusions, Intravenous (IV) Iron or rhEPO at Any Time Post-Baseline | Participants receiving additional therapies of blood transfusions, intravenous (IV) iron or rhEPO any time Post Baseline were analyzed. RhEPO was not applicable for the control arms since it was a planned therapy in those arms, hence presented as NA. (EudraCT only: A value of 99999 is used where no data is available or NA.) | From Day 1 up to Week 28 | 
| Number of Weeks Dose Withheld Because Hemoglobin (Hgb) Exceeded the Upper Limit | Number of Weeks dose was withheld because hemoglobin exceed the upper limit is presented as the number of participants with withheld dose during the time periods categorized by Weeks. | From Week 4 up to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prolyl hydroxylase inhibitor, pharmacokinetics, GSK1278863, Anemia, hemoglobin, erythropoiesis stimulating agents, Chronic kidney disease