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)

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

Sponsors

Lead Sponsor: GlaxoSmithKline

Source GlaxoSmithKline
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.

Overall Status Completed
Start Date November 21, 2016
Completion Date July 2, 2018
Primary Completion Date July 2, 2018
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) Weeks 40 to 52
Secondary Outcome
Measure 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) Weeks 40 to 52
Change From Baseline in Hgb (Hgb Increase Rate) at Week 4 Baseline and Week 4
Percentage of Participants by Hgb Change From Baseline Category at Week 4 Week 4
Distribution of Daprodustat Dose Level by Visit Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44, and 48)
Distribution of Darbepoetin Alfa Dose Level by Visit 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 Up to Week 52
Number of Dose Adjustments for Daprodustat Up to Week 52
Hgb Values at Each Assessment Visit 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 (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 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) Weeks 40 to 52
Number of Participants Who Had an Hgb Level of Less Than 7.5 g/dL Up to Week 52
Number of Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks Up to Week 52
Number of Participants Who Had an Hgb Level of More Than 13.0 g/dL Up to Week 52
Number of Episodes With Hgb Level of More Than 13.0 g/dL Up to Week 52
Area Under Plasma Concentration Curve From Time Zero to 4 Hours (AUC [0 - 4]) of Plasma Daprodustat 0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24
Maximum Concentration (Cmax) of Plasma Daprodustat 0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24
Enrollment 271
Condition
Intervention

Intervention Type: Drug

Intervention Name: Daprodustat small

Description: 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

Arm Group Label: Daprodustat

Intervention Type: Drug

Intervention Name: Daprodustat small placebo

Description: Available as 7.0 mm round, standard biconvex, white film coated tablets containing no daprodustat

Arm Group Label: Darbepoetin alfa

Intervention Type: Drug

Intervention Name: Daprodustat large

Description: Available as 9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of daprodustat as active ingredient

Arm Group Label: Daprodustat

Intervention Type: Drug

Intervention Name: Daprodustat large placebo

Description: Available as 9.0 mm round, standard biconvex, white film coated tablets containing no daprodustat

Arm Group Label: Darbepoetin alfa

Intervention Type: Drug

Intervention Name: Darbepoetin alfa

Description: 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.

Arm Group Label: Darbepoetin alfa

Intervention Type: Drug

Intervention Name: Darbepoetin alfa placebo

Description: Available as 0.5 mL plastic PFS for IV injection containing no darbepoetin alfa in a clear and colorless solution.

Arm Group Label: Daprodustat

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.

Gender: All

Minimum Age: 20 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
GSK Clinical Trials Study Director GlaxoSmithKline
Location
Facility:
GSK Investigational Site | Aichi, 441-8023, Japan
GSK Investigational Site | Aichi, 446-0053, Japan
GSK Investigational Site | Aichi, 446-0065, Japan
GSK Investigational Site | Aichi, 454-0932, Japan
GSK Investigational Site | Aichi, 455-0021, Japan
GSK Investigational Site | Aichi, 462-0802, Japan
GSK Investigational Site | Aichi, 486-8510, Japan
GSK Investigational Site | Chiba, 276-0031, Japan
GSK Investigational Site | Ehime, 790-0962, Japan
GSK Investigational Site | Ehime, 792-0812, Japan
GSK Investigational Site | Fukui, 918-8503, Japan
GSK Investigational Site | Fukuoka, 804-0094, Japan
GSK Investigational Site | Fukuoka, 811-0120, Japan
GSK Investigational Site | Fukuoka, 811-0213, Japan
GSK Investigational Site | Fukuoka, 818-0083, Japan
GSK Investigational Site | Fukushima, 963-8002, Japan
GSK Investigational Site | Fukushima, 963-8071, Japan
GSK Investigational Site | Gunma, 370-0615, Japan
GSK Investigational Site | Gunma, 372-0817, Japan
GSK Investigational Site | Gunma, 375-0024, Japan
GSK Investigational Site | Hokkaido, 004-0814, Japan
GSK Investigational Site | Hokkaido, 007-0803, Japan
GSK Investigational Site | Hokkaido, 073-0022, Japan
GSK Investigational Site | Hokkaido, 073-0196, Japan
GSK Investigational Site | Ibaraki, 300-0062, Japan
GSK Investigational Site | Ibaraki, 302-0011, Japan
GSK Investigational Site | Ibaraki, 305-0861, Japan
GSK Investigational Site | Kagawa, 761-8024, Japan
GSK Investigational Site | Kanagawa, 224-0032, Japan
GSK Investigational Site | Kanagawa, 227-0046, Japan
GSK Investigational Site | Kanagawa, 234-0054, Japan
GSK Investigational Site | Kanagawa, 235-0045, Japan
GSK Investigational Site | Kyoto, 613-0034, Japan
GSK Investigational Site | Miyagi, 981-0954, Japan
GSK Investigational Site | Nagano, 390-0821, Japan
GSK Investigational Site | Nagano, 390-1401, Japan
GSK Investigational Site | Nagano, 399-8292, Japan
GSK Investigational Site | Okayama, 714-0043, Japan
GSK Investigational Site | Osaka, 543-0052, Japan
GSK Investigational Site | Osaka, 547-0024, Japan
GSK Investigational Site | Osaka, 584-0082, Japan
GSK Investigational Site | Osaka, 594-0076, Japan
GSK Investigational Site | Saitama, 348-0045, Japan
GSK Investigational Site | Shizuoka, 424-0012, Japan
GSK Investigational Site | Tokyo, 158-0094, Japan
GSK Investigational Site | Tokyo, 169-0075, Japan
GSK Investigational Site | Toyama, 930-0065, Japan
GSK Investigational Site | Toyama, 938-8502, Japan
GSK Investigational Site | Yamagata, 990-0834, Japan
GSK Investigational Site | Yamaguchi, 755-0155, Japan
Location Countries

Japan

Verification Date

November 2019

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Daprodustat

Type: Experimental

Description: Subjects will receive oral daprodustat once daily and intravenous (IV) darbepoetin alfa placebo once weekly for 52 weeks

Label: Darbepoetin alfa

Type: Active Comparator

Description: Subjects will receive IV darbepoetin alfa once weekly and oral daprodustat placebo once daily for 52 weeks

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov