Phase III Study of GSK1278863 in Japanese Non-dialysis (ND) and Peritoneal Dialysis (PD) Subjects With Renal Anemia

NCT ID: NCT02791763

Last Updated: 2021-05-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 355 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-06
• Study Completion Date: 2018-10-26

Brief Summary

This is a Phase III, open-label, active-controlled, parallel-group, multi-center study to compare the efficacy and safety of GSK1278863 administered for 52 weeks versus epoetin beta pegol in approximately 286 Japanese ND and 50 PD subjects with renal anemia. The study will consist of three cohorts. Cohort 1 and Cohort 3 will consist of ND subjects (Erythropoiesis-Stimulating Agent [ESA] users and ESA non-users) randomized to receive GSK1278863 or epoetin beta pegol in a ratio of 1:1. PD subjects will be enrolled into Cohort 2 and will receive GSK1278863. This study consists of a 4-week screening phase, a 52-week treatment phase (including primary efficacy evaluation period [Weeks 40 to 52]), and a 4-week follow-up phase following the treatment phase. The primary objective of this study is to demonstrate non-inferiority of GSK1278863 to epoetin beta pegol based on mean hemoglobin (Hgb) during the primary efficacy evaluation period in ND subjects. ESA non-users from Cohort 1 will be excluded from the primary efficacy analysis. Study results will be used as pivotal study data for an NDA submitted for GSK1278863 for the treatment of renal anemia in Japan.

Conditions

Anaemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Daprodustat in ND participants

Eligible ND participants will receive oral daprodustat (1, 2, 4, 6, 8, 12, 18 or 24 milligrams \[mg\] as recommended) dose once daily for 52 weeks.

Group Type: EXPERIMENTAL

1 to 4 mg tablets of GSK1278863

Intervention Type: DRUG

7.0 millimeters (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient, to be orally administered once daily.

6 mg GSK1278863 tablet

Intervention Type: DRUG

9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of GSK1278863 as active ingredient, to be orally administered once daily.

Epoetin beta pegol in ND participants

Eligible ND participants will receive subcutaneous (SC) epoetin beta pegol (25, 50, 75, 100, 150, 200 or 250 microgram \[µg\] as recommended) dose once every 2 or 4 weeks for 52 weeks.

Group Type: ACTIVE_COMPARATOR

Epoetin beta pegol

Intervention Type: DRUG

An injectable formulation containing 25 micrograms µg, 50 µg, 75 µg, 100 µg, 150 µg, 200 µg, or 250 µg of epoetin beta pegol per syringe (0.3 mL), supplied as a glass syringe prefilled with epoetin beta pegol solution (clear colorless to pale yellow). Epoetin beta pegol will be subcutaneously administered once every 2 or 4 weeks.

Daprodustat in PD participants

Eligible PD participants will receive oral daprodustat (1, 2, 4, 6, 8, 12, 18 or 24 mg as recommended) dose once daily for 52 weeks.

Group Type: EXPERIMENTAL

1 to 4 mg tablets of GSK1278863

Intervention Type: DRUG

7.0 millimeters (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient, to be orally administered once daily.

6 mg GSK1278863 tablet

Intervention Type: DRUG

9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of GSK1278863 as active ingredient, to be orally administered once daily.

Interventions

1 to 4 mg tablets of GSK1278863

7.0 millimeters (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of GSK1278863 as active ingredient, to be orally administered once daily.

Intervention Type: DRUG

6 mg GSK1278863 tablet

9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of GSK1278863 as active ingredient, to be orally administered once daily.

Intervention Type: DRUG

Epoetin beta pegol

An injectable formulation containing 25 micrograms µg, 50 µg, 75 µg, 100 µg, 150 µg, 200 µg, or 250 µg of epoetin beta pegol per syringe (0.3 mL), supplied as a glass syringe prefilled with epoetin beta pegol solution (clear colorless to pale yellow). Epoetin beta pegol will be subcutaneously administered once every 2 or 4 weeks.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age (at the time of informed consent): >=20 years of age
• Screening verification only: Stage of chronic kidney disease (CKD) (ND subjects only): CKD stages 3, 4, and 5 defined by estimated glomerular filtration rate (eGFR) using the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) formula
• Dialysis:

• Not on dialysis for at least 12 weeks prior to screening (ND subjects)
• On peritoneal dialysis (PD subjects)
• Use of ESA:

• ESA non-users: Have not used ESAs for 8 weeks prior to screening
• ESA users: Have used the same ESA for 8 weeks prior to screening. However, in the ND subjects, the dose of darbepoetin alfa or epoetin beta pegol must be stable (administered once every 4 weeks and up to one-step dose change during 8 weeks prior to screening).
• Hgb: Determined at the site using an Hgb analyzer

• ESA non-users: >=8.0 g/dL and <11.0 g/dL
• ESA users: >=9.0 g/dL and <=13.0 g/dL
• Iron parameters: Ferritin >100 nanograms per milliliters (ng/mL) or transferrin saturation (TSAT) >20% (screening verification only)
• Gender (screening verification only): Female or male. Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in urine or serum], not breast-feeding, and meet at least one of the following:

1. Females of non-childbearing potential are defined as follows:

• Pre-menopausal with at least one of the following and no plans to utilize assisted reproductive techniques (e.g., in vitro fertilization 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: 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 postmenopausal follicle stimulating hormone [FSH] and estradiol concentrations is confirmatory [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.

2. Females of childbearing potential must agree to comply with one of the contraception methods listed as requirements in "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 (for subjects randomized to the GSK1278863 group) or 7 weeks after the last dose of study treatment (for subjects randomized to the Epoetin beta pegol group).

• 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 as specified in Protocol.

Exclusion Criteria

Chronic kidney disease (CKD)-related criteria

• Dialysis

• Cohort 1 and Cohort 3: Start or plan to initiate dialysis during the study
• Cohort 2: Plan to stop peritoneal dialysis or start hemodialysis during the study
• 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 8 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 8 weeks prior to 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
• QT interval corrected for heart rate (QTc) (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):

• (Screening verification only) Alanine transaminase (ALT) >2 times upper limit of normal (ULN)
• (Screening verification only) Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%)
• 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: Stable liver disease (including asymptomatic gallstones, chronic hepatitis B/C, or Gilbert's syndrome) is acceptable if the subject otherwise meets entry criteria..
• Malignancy: History of malignancy within 2 years prior to screening, or currently receiving treatment for cancer, (PD subjects only) complex renal cystic >3 centimeters (cm) (II F, III or IV based on the Bosniak classification) Note (ND subjects and PD subjects): The only exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated >=8 weeks before screening.
• In the opinion of the investigator, Hgb increase to the target range (11.0-13.0 g/dL) is medically risky.

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 Note: Oral iron is acceptable. However, the same dose regimen must be used throughout the screening phase and from Day 1 to Week 4. Antihyperphosphatemic agents containing iron (e.g., ferric citrate hydrate) are also acceptable only if used for at least 12 weeks prior to screening. However, they must be continued throughout the screening phase from Day 1 to Week 4.
• Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product or epoetin beta pegol
• 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 2C8 [CYP2C8])
• 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 GSK1278863: Any prior treatment with GSK1278863 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.

• Minimum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Aichi, , Japan

GSK Investigational Site

Aichi, , Japan

GSK Investigational Site

Aichi, , Japan

GSK Investigational Site

Aichi, , Japan

GSK Investigational Site

Chiba, , Japan

GSK Investigational Site

Chiba, , Japan

GSK Investigational Site

Ehime, , Japan

GSK Investigational Site

Fukui, , Japan

GSK Investigational Site

Fukuoka, , Japan

GSK Investigational Site

Fukuoka, , Japan

GSK Investigational Site

Fukushima, , Japan

GSK Investigational Site

Gifu, , Japan

GSK Investigational Site

Gifu, , Japan

GSK Investigational Site

Hiroshima, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Ibaraki, , Japan

GSK Investigational Site

Ibaraki, , Japan

GSK Investigational Site

Ibaraki, , Japan

GSK Investigational Site

Ishikawa, , Japan

GSK Investigational Site

Ishikawa, , Japan

GSK Investigational Site

Kagoshima, , Japan

GSK Investigational Site

Kagoshima, , Japan

GSK Investigational Site

Kagoshima, , Japan

GSK Investigational Site

Kanagawa, , Japan

GSK Investigational Site

Kanagawa, , Japan

GSK Investigational Site

Kanagawa, , Japan

GSK Investigational Site

Kanagawa, , Japan

GSK Investigational Site

Kumamoto, , Japan

GSK Investigational Site

Kumamoto, , Japan

GSK Investigational Site

Kyoto, , Japan

GSK Investigational Site

Kyoto, , Japan

GSK Investigational Site

Kyoto, , Japan

GSK Investigational Site

Nagano, , Japan

GSK Investigational Site

Nagano, , Japan

GSK Investigational Site

Numakunai, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Ōita, , Japan

GSK Investigational Site

Saitama, , Japan

GSK Investigational Site

Saitama, , Japan

GSK Investigational Site

Shiga, , Japan

GSK Investigational Site

Shizuoka, , Japan

GSK Investigational Site

Tokushima, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Tottori, , Japan

GSK Investigational Site

Toyama, , Japan

GSK Investigational Site

Toyama, , Japan

GSK Investigational Site

Toyama, , Japan

Countries

Japan

References

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.

Reference Type: DERIVED

PMID: 36005278 (View on PubMed)

Nangaku M, Hamano T, Akizawa T, Tsubakihara Y, Nagai R, Okuda N, Kurata K, Nagakubo T, Jones NP, Endo Y, Cobitz AR. Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial. Am J Nephrol. 2021;52(1):26-35. doi: 10.1159/000513103. Epub 2021 Feb 9.

Reference Type: DERIVED

PMID: 33561857 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

201753

Identifier Type: -

Identifier Source: org_study_id