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

GlaxoSmithKline355 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

355

Conditions

Anaemia

Interventions

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) in ND Participants

The mean hemoglobin during the primary efficacy evaluation period in ND participants was estimated by a statistical model using Mixed Model Repeated Measures (MMRM).

Time frame: Weeks 40 to 52

Secondary Outcomes

Number of ND Participants With Mean Hgb in the Target Range (11.0-13.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)

ND participants with observed mean Hgb within the target range during the primary efficacy evaluation period were summarized. Responders were defined as the participants with the mean Hgb within target range during the primary efficacy evaluation period.

Time frame: Weeks 40 to 52

Percentage of ND Participants With Mean Hgb in the Target Range (11.0-13.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)

The percentage of ND participants with observed mean Hgb within the target range during the primary efficacy evaluation period was summarized. Responders were defined as the participants with the mean Hgb within target range during the primary efficacy evaluation period.

Time frame: Weeks 40 to 52

Change From Baseline in Hgb at Week 4 in ND Participants

Baseline Hgb value was the value from the Day 1 visit. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data for change from Baseline in Hgb at Week 4 in ND participants is presented.

Time frame: Baseline (Day 1) and Week 4

Change From Baseline in Hgb at Week 4 in PD Participants

Time frame: Baseline (Day 1) and Week 4

Number of ND Participants by Hgb Change From Baseline Category at Week 4

Baseline Hgb value was the value from the Day 1 visit. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Number of participants by Hgb change from Baseline is categorized to \<=-2.0, \>-2.0 and \<=-1.0, \>-1.0 and \<=0, \>0 and \<=1.0, \>1.0 and \<=2.0, \>2.0 g/dL, then is additionally categorized to within +/- 1.0 g/dL and over +/- 2.0 g/dL. Number of participants have been included in more than one category at Week 4.

Time frame: Baseline (Day 1) and Week 4

Percentage of ND Participants by Hgb Change From Baseline Category at Week 4

Time frame: Baseline (Day 1) and Week 4

Number of PD Participants by Hgb Change From Baseline Category at Week 4

Time frame: Baseline (Day 1) and Week 4

Percentage of PD Participants by Hgb Change From Baseline Category at Week 4

Time frame: Baseline (Day 1) and Week 4

Daprodustat Dose Level by Visit in ND Participants

Daprodustat dose level at each assessment visit for ND participants is presented using 25th percentile (P25), median, and 75th percentile (P75).

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44 and 48

Epoetin Beta Pegol Dose Level by Visit in ND Participants

Dose of epoetin beta pegol at a scheduled visit was converted to dose per 4 weeks when the dose frequency was every 2 weeks. Epoetin beta pegol dose level at each assessment visit for ND participants is presented using 25th percentile (P25), median, and 75th percentile (P75).

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44 and 48

Daprodustat Dose Level by Visit in PD Participants

Daprodustat dose level at each assessment visit for PD participants is presented using 25th percentile (P25), median, and 75th percentile (P75).

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44 and 48

Duration of Treatment Interruption Due to Hgb >13 g/dL in ND Participants

The duration (in days) of treatment interruption due to Hgb \>13 g/dL per participant was summarized descriptively on participants with a period of treatment interruption due to Hgb \>13 g/dL.

Time frame: Up to Week 52

Duration of Treatment Interruption Due to Hgb >13 g/dL in PD Participants

The duration (in days) of treatment interruption due to Hgb \>13 g/dL per participant was summarized descriptively on participants with a period of treatment interruption due to Hgb \>13 g/dL.

Time frame: Up to Week 52

Number of Dose Adjustments in ND Participants

Number of dose adjustments in ND participants is presented.

Time frame: Up to Week 52

Number of Dose Adjustments in PD Participants

Number of dose adjustments in PD participants is presented.

Time frame: Up to Week 52

Hgb Values at Each Assessment Visit in ND Participants

Hgb values at each assessment visit for ND participants is presented.

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Hgb Values at Each Assessment Visit in PD Participants

Hgb values at each assessment visit for PD participants is presented.

Time frame: 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 in ND Participants

Time frame: 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 in PD Participants

Time frame: Baseline (Day 1), Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Number of ND Participants Who Had Hgb Level Within the Target Range (11.0-13.0 g/dL) at Each Assessment Visit

Number of ND participants with Hgb level within the target range (11.0 to 13.0 g/dL) are summarized at each assessment visit.

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Percentage of ND Participants Who Had Hgb Level Within the Target Range (11.0-13.0 g/dL) at Each Assessment Visit

Percentage of ND participants with Hgb level within the target range (11.0 to 13.0 g/dL) are summarized at each assessment visit.

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Number of PD Participants Who Had Hgb Level Within the Target Range (11.0-13.0 g/dL) at Each Assessment Visit

Number of PD participants with Hgb level within the target range (11.0 to 13.0 g/dL) are summarized at each assessment visit.

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Percentage of PD Participants Who Had Hgb Level Within the Target Range (11.0-13.0 g/dL) at Each Assessment Visit

Percentage of PD participants with Hgb level within the target range (11.0 to 13.0 g/dL) are summarized at each assessment visit.

Time frame: Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Percentage of Time With Hgb Within the Target Range (11.0 to 13.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) in ND Participants

Mean percentage of time with Hgb within the target range (11.0 to 13.0 g/dL) is summarized during the primary efficacy evaluation period (Weeks 40 to 52).

Time frame: Weeks 40 to 52

Percentage of Time With Hgb Within the Target Range (11.0 to 13.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) in PD Participants

Mean percentage of time with Hgb within the target range (11.0 to 13.0 g/dL) is summarized during the primary efficacy evaluation period (Weeks 40 to 52).

Time frame: Weeks 40 to 52

Time to Reach the Lower Target Hgb Level (11.0 g/dL) in ND Participants

The time (in days) to reach the lower target Hgb level (11.0 g/dL) was summarized using 25th percentile (P25), median, and 75th percentile (P75) by Kaplan-Meier method. Participants who did not reach the lower Hgb target were considered as censored cases. Participants who were randomized as Hgb \>= 11.0 g/dL were excluded in this summary.

Time frame: Up to week 52

Time to Reach the Lower Target Hgb Level (11.0 g/dL) in PD Participants

Time frame: Up to week 52

Number of ND Participants Who Had an Hgb Level of Less Than 7.5 g/dL

Number of ND participants who had an Hgb level of less than 7.5 g/dL is presented.

Time frame: Up to week 52

Percentage of ND Participants Who Had an Hgb Level of Less Than 7.5 g/dL

Percentage of ND participants who had an Hgb level of less than 7.5 g/dL is presented.

Time frame: Up to week 52

Number of PD Participants Who Had an Hgb Level of Less Than 7.5 g/dL

Number of PD participants who had an Hgb level of less than 7.5 g/dL is presented.

Time frame: Up to week 52

Percentage of PD Participants Who Had an Hgb Level of Less Than 7.5 g/dL

Percentage of PD participants who had an Hgb level of less than 7.5 g/dL is presented.

Time frame: Up to week 52

Number of ND Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks

Number of ND participants who had an Hgb increase of more than 2 g/dL over any 4 weeks is presented.

Time frame: Up to week 52

Percentage of ND Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks

Percentage of ND participants who had an Hgb increase of more than 2 g/dL over any 4 weeks is presented.

Time frame: Up to week 52

Number of PD Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks

Number of PD participants who had an Hgb increase of more than 2 g/dL over any 4 weeks is presented.

Time frame: Up to week 52

Percentage of PD Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks

Percentage of PD participants who had an Hgb increase of more than 2 g/dL over any 4 weeks is presented.

Time frame: Up to week 52

Number of ND Participants Who Had an Hgb Level of More Than 13.0 g/dL

Number of ND participants who had an Hgb level of more than 13.0 g/dL is presented.

Time frame: Up to week 52

Percentage of ND Participants Who Had an Hgb Level of More Than 13.0 g/dL

Percentage of ND participants who had an Hgb level of more than 13.0 g/dL is presented.

Time frame: Up to week 52

Number of PD Participants Who Had an Hgb Level of More Than 13.0 g/dL

Number of PD participants who had an Hgb level of more than 13.0 g/dL is presented.

Time frame: Up to week 52

Percentage of PD Participants Who Had an Hgb Level of More Than 13.0 g/dL

Percentage of PD participants who had an Hgb level of more than 13.0 g/dL is presented.

Time frame: Up to week 52

Number of Episodes With Hgb Level of More Than 13.0 g/dL in ND Participants

Number of episodes with Hgb level of more than 13.0 g/dL in ND participants is presented.

Time frame: Up to week 52

Number of Episodes With Hgb Level of More Than 13.0 g/dL in PD Participants

Number of episodes with Hgb level of more than 13.0 g/dL in PD participants is presented.

Time frame: Up to week 52

Monthly Average Dose of Oral Iron During the Treatment Period in ND Participants

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. Monthly average oral iron = Total oral iron dose (mg) / (duration in days / 30.4375 days). Monthly average dose of oral iron during the treatment period in ND participants is presented.

Time frame: Up to Week 52

Monthly Average Dose of Oral Iron During the Treatment Period in PD Participants

Time frame: Up to Week 52

Monthly Average Dose of Oral Iron During the Primary Efficacy Evaluation Period in ND Participants

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. Monthly average oral iron dose during the primary efficacy evaluation period (Weeks 40 to 52) = Total oral iron dose (mg) during the primary efficacy evaluation period / (duration in the period in days / 30.4375 days). Monthly average dose of oral iron during the primary efficacy evaluation period in ND participants is presented.

Time frame: Weeks 40 to 52

Monthly Average Dose of Oral Iron During the Primary Efficacy Evaluation Period in PD Participants

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. Monthly average oral iron dose during the primary efficacy evaluation period (Weeks 40 to 52) = Total oral iron dose (mg) during the primary efficacy evaluation period / (duration in the period in days / 30.4375 days). Monthly average dose of oral iron during the primary efficacy evaluation period in PD participants is presented.

Time frame: Weeks 40 to 52

Number of ND Participants Who Used Oral Iron During the Treatment Period

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. The number of ND participants who used oral iron during the treatment period were summarized.

Time frame: Up to week 52

Number of PD Participants Who Used Oral Iron During the Treatment Period

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. The number of PD participants who used oral iron during the treatment period were summarized.

Time frame: Up to week 52

Percentage of ND Participants Who Used Oral Iron During the Treatment Period

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. The percentage of ND participants who used oral iron during the treatment period were summarized.

Time frame: Up to week 52

Percentage of PD Participants Who Used Oral Iron During the Treatment Period

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. The percentage of PD participants who used oral iron during the treatment period were summarized.

Time frame: Up to week 52

Number of ND Participants Who Used Oral Iron During the Primary Efficacy Evaluation Period

Time frame: Weeks 40 to 52

Number of PD Participants Who Used Oral Iron During the Primary Efficacy Evaluation Period

Time frame: Weeks 40 to 52

Percentage of ND Participants Who Used Oral Iron During the Primary Efficacy Evaluation Period

Time frame: Weeks 40 to 52

Percentage of PD Participants Who Used Oral Iron During the Primary Efficacy Evaluation Period

Supplemental iron therapy were received by participants if required during treatment period. Participants who used ferric citrate were counted as oral iron use. The percentage of PD participants who used oral iron during the primary efficacy evaluation period (Weeks 40 to 52) were summarized.

Time frame: Weeks 40 to 52

Change From Baseline in Ferritin in ND Participants

Change from Baseline in Ferritin in ND participants was summarized at each assessment visit. The Baseline value was the latest pre-dose assessment (Day 1 pre-dose). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Adjusted mean and 95% confidence interval for change from Baseline in Ferritin is presented. For adjusted values, analysis was performed by MMRM with covariates of treatment, Baseline, visit, treatment-by-visit interaction and Baseline-by-visit interaction.