Clinical trial NCT02969655: 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)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anaemia
Keywords: Safety
Efficacy
Daprodustat
Chronic kidney disease
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-11-21
Enrollment: 271
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)
timeFrame: Weeks 40 to 52
Secondary outcomes:
measure: 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)
timeFrame: Weeks 40 to 52
measure: Change From Baseline in Hgb (Hgb Increase Rate) at Week 4
timeFrame: Baseline and Week 4
measure: Percentage of Participants by Hgb Change From Baseline Category at Week 4
timeFrame: Week 4
measure: Distribution of Daprodustat Dose Level by Visit
timeFrame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44, and 48)
measure: Distribution of Darbepoetin Alfa Dose Level by Visit
timeFrame: 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
measure: Duration of Treatment Interruption Due to Hgb >13 g/dL
timeFrame: Up to Week 52
measure: Number of Dose Adjustments for Daprodustat
timeFrame: Up to Week 52
measure: Hgb Values at Each Assessment Visit
timeFrame: Baseline (Day 1), Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52
measure: Change From Baseline in Hgb Values at Each Assessment Visit
timeFrame: Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52
measure: Percentage of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) at Each Assessment Visit
timeFrame: Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52
measure: Percentage of Time in Hgb Target Range (10.0 to 12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)
timeFrame: Weeks 40 to 52
measure: Number of Participants Who Had an Hgb Level of Less Than 7.5 g/dL
timeFrame: Up to Week 52
measure: Number of Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks
timeFrame: Up to Week 52
measure: Number of Participants Who Had an Hgb Level of More Than 13.0 g/dL
timeFrame: Up to Week 52
measure: Number of Episodes With Hgb Level of More Than 13.0 g/dL
timeFrame: Up to Week 52
measure: Area Under Plasma Concentration Curve From Time Zero to 4 Hours (AUC [0 - 4]) of Plasma Daprodustat
timeFrame: 0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24
measure: Maximum Concentration (Cmax) of Plasma Daprodustat
timeFrame: 0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Ehime
country: Japan
facility: GSK Investigational Site
city: Ehime
country: Japan
facility: GSK Investigational Site
city: Fukui
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukushima
country: Japan
facility: GSK Investigational Site
city: Fukushima
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Kagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kyoto
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Okayama
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Saitama
country: Japan
facility: GSK Investigational Site
city: Shizuoka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Toyama
country: Japan
facility: GSK Investigational Site
city: Toyama
country: Japan
facility: GSK Investigational Site
city: Yamagata
country: Japan
facility: GSK Investigational Site
city: Yamaguchi
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue T, Endo Y, Hara K, Cobitz AR. Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial. Clin J Am Soc Nephrol. 2020 Aug 7;15(8):1155-1165. doi: 10.2215/CJN.16011219. Epub 2020 Jul 28.
citation: Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.