A Study to Evaluate Efficacy and Safety of Daprodustat Compared to Darbepoetin Alfa in Japanese Hemodialysis (HD)-Dependent Subjects With Anemia Associated With Chronic Kidney Disease (CKD)

Study Overview
=================
Brief Summary
-----------------
Daprodustat is a drug that is currently being developed as a treatment for renal anemia . This study is to evaluate the efficacy and safety of daprodustat following a switch from erythropoiesis-stimulating agent (ESA) in Japanese HD subjects with renal anemia who are currently treated with ESA. The primary objective is to demonstrate non-inferiority of daprodustat to darbepoetin alfa. This study is a 52-week, Phase III, double-blind, active-controlled, parallel-group, multi-center study. The total duration of the study will be approximately 58 weeks including screening and follow-up.

Official Title
-----------------
A 52-week, Phase III, Double-blind, Active-controlled, Parallel-group, Multi-center Study to Evaluate Efficacy and Safety of Daprodustat Compared to Darbepoetin Alfa in Japanese Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease Who Are Currently ESA Users

Conditions
-----------------
Anaemia

Intervention / Treatment
-----------------
* Drug: Daprodustat small
* Drug: Daprodustat small placebo
* Drug: Daprodustat large
* Drug: Daprodustat large placebo
* Drug: Darbepoetin alfa
* Drug: Darbepoetin alfa placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Age (informed consent): >=20 years of age Dialysis: On HD or hemodiafiltration (HDF) given three times weekly for at least 12 weeks prior to screening ESAs: Use of one and the same ESA for 10 weeks prior to screening ESA dose: Darbepoetin alfa 10 to 60 μg per week, epoetin (including biosimilars) <=9000 international units (IU) per week, or epoetin beta pegol <=250 μg per 4 weeks Hgb:>=9.5 g/dL and <=12.5 g/dL. Determined at the site using an Hgb analyzer Iron parameters: Ferritin >100 nanogram (ng)/millilitre (mL) or transferrin saturation (TSAT) >20 percent (screening verification only) Gender (screening verification only): Female or male Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in serum], not breast-feeding, and meet at least one of the following: • Females of non-childbearing potential are defined as follows: Pre-menopausal with at least one of the following and no plans to utilise assisted reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer): History of bilateral tubal ligation or salpingectomy History of hysteroscopic tubal occlusion and postoperatively documented bilateral tubal obstruction History of hysterectomy History of bilateral oophorectomy Postmenopausal defined as A) females 60 years of age or older or B) In females < 60 years of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is confirmatory (see separately specified reference ranges)]. Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the most effective 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. • Females of childbearing potential must agree to comply with one of the contraception methods listed as requirements in GlaxoSmithKline (GSK) Listing of Most Effective Contraceptive Methods for Females of Childbearing Potential from 28 days prior to the first dose of study medication until the completion of the follow-up visit. Informed consent: Written informed consent, including adherence to the requirements and conditions specified in the consent form and the protocol, must be obtained from each subject. Exclusion Criteria CKD-related criteria Kidney transplant: Planned living-related kidney transplant during the study Anemia-related criteria Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic syndromes Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within 10 weeks prior to screening or during a period from screening to Day 1 Cardiovascular disease-related criteria Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed within 10 weeks prior to screening or during a period from screening to Day 1 Heart failure: Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system Corrected QT (QTc) Interval (screening verification only): QTc >500 milliseconds (msec); or QTc >530 msec in subjects with bundle branch block Note: QT interval corrected using the Bazett's formula (QTcB) will be used, and electrocardiogram (ECG) can be mechanically or manually read Other disease-related criteria: Liver disease (if any of the following occurs): Alanine transaminase (ALT) >2 upper limit of normal (ULN) Bilirubin >1.5×ULN (isolated bilirubin >1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35 percent) Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice, or cirrhosis) Malignancy: History of malignancy within 2 years prior to screening, currently receiving treatment for cancer, or complex kidney cyst >3 centimeters (cm) (II F, III or IV based on the Bosniak classification) Concomitant medication and other study treatment-related criteria Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 to Week 4 Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product. Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited during the study period [prohibited medications: strong inducers and inhibitor of Cytochrome P450 (CYP) 2C8]. Prior investigational product exposure: Use of an investigational agent within 30 days or five half lives of the investigational agent (whichever is longer) Prior treatment with daprodustat: Any prior treatment with daprodustat for a treatment duration of >30 days General health-related criteria Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator (or subinvestigator) considers would put the subject 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
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daprodustat<br>Subjects will receive oral daprodustat once daily and intravenous (IV) darbepoetin alfa placebo once weekly for 52 weeks | Drug: Daprodustat small<br>* Available as 7.0 millimeter (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of daprodustat as active ingredient<br>Drug: Daprodustat large<br>* Available as 9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of daprodustat as active ingredient<br>Drug: Darbepoetin alfa placebo<br>* Available as 0.5 mL plastic PFS for IV injection containing no darbepoetin alfa in a clear and colorless solution.<br>|
| Active Comparator: Darbepoetin alfa<br>Subjects will receive IV darbepoetin alfa once weekly and oral daprodustat placebo once daily for 52 weeks | Drug: Daprodustat small placebo<br>* Available as 7.0 mm round, standard biconvex, white film coated tablets containing no daprodustat<br>Drug: Daprodustat large placebo<br>* Available as 9.0 mm round, standard biconvex, white film coated tablets containing no daprodustat<br>Drug: Darbepoetin alfa<br>* Available as 0.5 mL plastic prefilled syringes (PFS) for IV injection each containing 10, 15, 20, 30, 40 or 60 mcg of darbepoetin alfa in a clear and colorless solution.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) | The mean hemoglobin during the Evaluation Period was estimated by a statistical model. | Weeks 40 to 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Mean Hgb in the Target Range (10.0-12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) | The percentage of participants with observed mean Hgb within the target range during the primary efficacy evaluation period was summarized. Odds ratio was estimated using a logistic regression and provided along with its 95% CI and a one-sided p-value. | Weeks 40 to 52 | 
| Change From Baseline in Hgb (Hgb Increase Rate) at Week 4 | Change from Baseline was calculated as the post-dose Week 4 visit value minus the Baseline value. | Baseline and Week 4 | 
| Percentage of Participants by Hgb Change From Baseline Category at Week 4 | Percentage of participants within each category were provided only for daprodustat and the categories were classified into 6 (i.e., <=-2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, >2 grams per deciliter [g/dL]). In addition, 'within 1.0 g/dL (i.e., <=-1 and >=1) and over 2.0 g/dL (i.e., <-2 and >2) categories were provided. | Week 4 | 
| Distribution of Daprodustat Dose Level by Visit | Distribution of dose level by visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for Daprodustat. Median along with the interquartile range (25th and 75th percentile) has been presented. | Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44, and 48) | 
| Distribution of Darbepoetin Alfa Dose Level by Visit | Distribution of dose level by visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for Darbepoetin Alfa. Median along with the interquartile range (25th and 75th percentile) has been presented. | Day 1, Weeks 2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48, and 50 | 
| Duration of Treatment Interruption Due to Hgb >13 g/dL | Duration of treatment interruption due to Hgb >13 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for the daprodustat group. | Up to Week 52 | 
| Number of Dose Adjustments for Daprodustat | Number of dose adjustments has been presented only for daprodustat. | Up to Week 52 | 
| Hgb Values at Each Assessment Visit | Hgb values at each assessment visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented. | Baseline (Day 1), Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52 | 
| Change From Baseline in Hgb Values at Each Assessment Visit | Baseline Hgb value was the value from the Day 1 visit. Change from Baseline was calcuated as the post-dose visit value minus the Baseline value. Change from Baseline Hgb values at each assessment visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented. | Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52 | 
| Percentage of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) at Each Assessment Visit | Percentage of participants with Hgb within the target range was summarized at each assessment visit by treatment group have been presented. | Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52 | 
| Percentage of Time in Hgb Target Range (10.0 to 12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) | Percentage of time in Hgb target range (10.0 to 12.0 g/dL) during the primary efficacy evaluation period (Weeks 40 to 52) for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented. | Weeks 40 to 52 | 
| Number of Participants Who Had an Hgb Level of Less Than 7.5 g/dL | If an initial Hgb value was less than 7.5 g/dL, measurement was repeated at the same study visit (using the same sample) to calculate the average. If the average met the Hgb stopping criteria, study treatment was permanently discontinued. Number of participants who had an Hgb level of less than 7.5 g/dL has been presented. | Up to Week 52 | 
| Number of Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks | Number of participants who had an Hgb increase of more than 2 g/dL over any 4 weeks for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have been presented. | Up to Week 52 | 
| Number of Participants Who Had an Hgb Level of More Than 13.0 g/dL | Number of participants who had an Hgb increase of more than 13 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have been presented. | Up to Week 52 | 
| Number of Episodes With Hgb Level of More Than 13.0 g/dL | Number of episodes with Hgb level of more than 13.0 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have been presented. | Up to Week 52 | 
| Area Under Plasma Concentration Curve From Time Zero to 4 Hours (AUC [0 - 4]) of Plasma Daprodustat | Blood samples for Pharmacokinetic (PK) analysis of daprodustat were collected as the time points provided. PK parameters were calculated by standard non-compartmental analysis according to current working practices and using the currently supported version of WinNonlin (version 6.3 or higher). NA indicates geometric co-efficient of variation could not be calculated as a single participant was analyzed. Data has been provided as a consolidated values for at all time-points (0,1,2,3,and 4 hours post-dose) as provided for a single value at Weeks 12 and 24 respectively. PK population comprised of all daprodustat-treated participants from whom PK samples were collected and analyzed. Data was not calculated for darbepoetin alfa group as the primary interest of analysis was Daprodustat and not comparator drug (darbepoetin alfa). Data is combined from Week 12 and Week 24 data. | 0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24 | 
| Maximum Concentration (Cmax) of Plasma Daprodustat | Blood samples for PK analysis of daprodustat were collected as the time points provided. PK parameters were calculated by standard non-compartmental analysis according to current working practices and using the currently supported version of WinNonlin (version 6.3 or higher). Data has been provided as a consolidated values for at all time-points (0,1,2,3,and 4 hours post-dose) as provided for a single value at Weeks 12 and 24 respectively. Data was not calculated for darbepoetin alfa group as the primary interest of analysis was Daprodustat and not comparator drug (darbepoetin alfa). Data is combined from Week 12 and Week 24 data. | 0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Safety, Efficacy, Daprodustat, Chronic kidney disease