Clinical trial NCT02829320: Efficacy and Safety Study of GSK1278863 in Japanese Hemodialysis Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Taking Erythropoiesis Stimulating Agents
Official title: A 24-week, Phase III, Open-label, Non-comparative, Multi-center Study to Evaluate Efficacy and Safety of GSK1278863 in Japanese Hemodialysis Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Taking Erythropoiesis Stimulating Agents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anaemia
Keywords: efficacy
hemodialysis (HD)
hemoglobin (Hgb)
erythropoiesis-stimulating agents (ESAs)
GSK1278863
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-07-12
Enrollment: 28
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This 24-week, Phase 3, open-label, non-comparative, multicentre study aims to evaluate the efficacy and safety of GSK1278863 in Japanese hemodialysis (HD) patients with renal anemia not using erythropoiesis-stimulating agents (ESAs). The primary objective is to evaluate the initial response to GSK1278863 measured by hemoglobin (Hgb) levels in HD patients not using ESAs enrolled in this study. The study is designed to evaluate the appropriateness of the starting dose of GSK1278863 and of the GSK1278863 dose adjustment regimen to achieve or maintain the target Hgb levels. This study will consist of a 4-week screening period, a 24-week treatment period (4-week fixed-dose period and a 20-week dose adjustment period), and a 2- to 4-week follow-up period.


Eligibility criteria: Inclusion Criteria:

* Age (at the time of informed consent): \>=20 years
* Dialysis: Patients on hemodialysis (HD) or hemodiafiltration (HDF)
* Use of any erythropoiesis stimulating agent (ESA): Newly started dialysis (Dialysis newly started \<12 weeks before screening): Patients not using ESAs after the start of dialysis; Maintenance dialysis (Dialysis started \>=12 weeks before screening): Patients not using ESAs within 8 weeks before screening (including interruption of ESA therapy)
* Hemoglobin (Hgb): \>=8.0 to \<10.0 g/dL (measured using a point-of-care Hgb measurement device at the study site on Day 1)
* Iron parameter: Ferritin \>100 nanograms (ng)/milliliter (mL) or transferrin saturation (TSAT) \>20% (at screening only)
* Gender (at screening only): Female or male.

A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotropin \[hCG\] test for females of reproductive potential \[FRP\] only), not breastfeeding, and at least one of the following conditions applies:

* Females of non-reproductive potential defined as: Pre-menopausal with one of the following and no plans to utilise assisted reproductive techniques (example \[e.g.\], in vitro fertilisation or donor embryo transfer): documented bilateral tubal ligation or salpingectomy; documented hysteroscopic tube occlusion procedure with follow-up confirmation of bilateral tubal occlusion; hysterectomy; documented bilateral oophorectomy
* Post-menopausal defined as females 60 years of age or older or In females \<60 years of age, 12 months of spontaneous amenorrhea (In questionable cases, a blood sample with simultaneous follicle stimulating hormone \[FSH\] and estradiol levels consistent with menopause is confirmatory \[the reference values are provided separately\]). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly 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 enrollment.

Females of reproductive potential who agree to follow one of the options listed in the "GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential" from 28 days before the first dose of study treatment until completion of the follow-up visit.

* Informed consent: Subjects who can provide written informed consent to the study, involving compliance with the requirements and patient responsibilities stated in the consent form and the protocol.

Exclusion Criteria:

CKD related criteria

* Kidney transplant: Planned living kidney transplant during the study period Anemia-related criteria
* Aplasia: History of bone marrow aplasia or pure red cell aplasia
* Other causes of anemia: Pernicious anemia, thalassaemia, sickle cell disease, or myelodysplastic syndrome
* Gastrointestinal bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding within 8 weeks before screening or during a period from screening to Day 1.

Cardiovascular disease-related criteria

* History of myocardial infarction, acute coronary syndrome, stroke or transient ischemic attack: Diagnosed within 8 weeks before screening or during a period from screening to Day 1.
* Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system
* Corrected QT interval (QTc) (at screening only): QTc \>500 milliseconds (msec), or QTc \>530 msec in subject with bundle branch block. Note: Corrected QT interval using Bazett's formula (QTcB) (machine-read or manually) will be used.

Other disease-related criteria

* Liver disease (if any of the following occurs):

  * Alanine transaminase (ALT) \>2x upper limit of normal (ULN)
  * Bilirubin \>1.5xULN (If bilirubin fractions are measured and direct bilirubin is \<35%, isolated bilirubin \>1.5xULN will be acceptable.)
  * Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice, or cirrhosis). Note: The only exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=8 weeks before screening.
* Malignancy: History of malignancy within the two years prior to screening, known complex kidney cyst \>3 centimeters (cm) (II F, III or IV based on the Bosniak classification) or currently receiving treatment for cancer. Note: The only exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=8 weeks before screening.

Concomitant medications and other study treatment-related criteria

* Iron medication: Planned use of any intravenous iron during the screening period or from Day 1 to Week 4.

Note:

* Patients on oral iron may be enrolled if the iron dose regimen is unchanged during the screening period and from Day 1 to Week 4.
* Patients on anti-hyperphosphatemia medication containing iron (e.g., ferric citrate hydrate) for at least 12 weeks before screening may be enrolled if the medication is continued during the screening and from Day 1 to Week 4.

  * Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to any excipients in the investigational product
  * Drugs and dietary supplements: Current use of prohibited prescription drugs, non-prescription drugs, or dietary supplements or planned use of any of these drugs during the study period (prohibited drugs: strong cytochrome P450 (CYP)2C8 inducers and inhibitors)
  * Exposure to any other investigational product: Use of an investigational product within the past 30 days or five half lives of that investigational product (whichever is longer).
  * Prior treatment with GSK1278863: Prior treatment with GSK1278863 for \>30 days General health-related criteria
  * Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator 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: Change From Baseline in Hgb at Week 4
timeFrame: Baseline and Week 4
measure: Number of Participants by Hgb Change From Baseline Category at Week 4
timeFrame: Baseline and Week 4
Secondary outcomes:
measure: Hgb Values at the Indicated Time Points
timeFrame: Up to Week 24
measure: Change From Baseline in Hgb at the Indicated Time Points
timeFrame: Baseline and up to Week 24
measure: Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL)
timeFrame: Up to Week 24
measure: Time to Reach the Lower Target Hgb Level (10.0 g/dL)
timeFrame: Up to Week 24
measure: Number of Participants Who Had Hgb Level of Less Than 7.5 g/dL
timeFrame: Up to Week 24
measure: Number of Participants Who Had Hgb Increase of More Than 2 g/dL Over Any 4 Weeks
timeFrame: Up to Week 24
measure: Number of Participants Who Had Hgb Level of More Than 13.0 g/dL
timeFrame: Up to Week 24
measure: Number of Episodes of Achieving Hgb Level of More Than 13.0 g/dL
timeFrame: Up to Week 24
measure: Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863
timeFrame: 1, 2, 3 and 4 hours post dose at Weeks 12 and 24
measure: Maximum Observed Concentration (Cmax) of GSK1278863
timeFrame: 1, 2, 3 and 4 hours post dose at Weeks 12 and 24
measure: Monthly Average Dose of Intravenous (IV) Iron During the Treatment Period
timeFrame: Up to Week 24
measure: Number of Participants Who Used Iron During the Treatment Period
timeFrame: Up to Week 24
measure: Change From Baseline in Ferritin
timeFrame: Baseline and up to Week 24
measure: Percent Change From Baseline in TSAT
timeFrame: Baseline and up to Week 24
measure: Percent Change From Baseline in Hepcidin
timeFrame: Baseline and up to Week 24
measure: Change From Baseline in Serum Iron
timeFrame: Baseline and up to Week 24
measure: Change From Baseline in Total Iron Binding Capacity (TIBC)
timeFrame: Baseline and up to Week 24
measure: Dose Level of GSK1278863 at Indicated Time Points
timeFrame: Up to Week 24
measure: Number of Participants With Frequency of Dose Adjustments
timeFrame: Up to Week 24
measure: Duration of Treatment Interruption Due to Hgb >13 g/dL
timeFrame: Up to Week 24
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Fukuoka
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: Kagoshima
country: Japan
facility: GSK Investigational Site
city: Kumamoto
country: Japan
facility: GSK Investigational Site
city: Kyoto
country: Japan
facility: GSK Investigational Site
city: Mie
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Oita
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Shiga
country: Japan
facility: GSK Investigational Site
city: Yamagata
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Tsubakihara Y, Akizawa T, Nangaku M, Onoue T, Yonekawa T, Matsushita H, Endo Y, Cobitz A. A 24-Week Anemia Correction Study of Daprodustat in Japanese Dialysis Patients. Ther Apher Dial. 2020 Apr;24(2):108-114. doi: 10.1111/1744-9987.12962. Epub 2019 Aug 13.