Anaemia
Conditions
Keywords
efficacy, hemodialysis (HD), hemoglobin (Hgb), erythropoiesis-stimulating agents (ESAs), GSK1278863
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.
Interventions
DRUGGSK1278863
GSK1278863 will be provided as round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, 4 mg or 6 mg of GSK1278863 as active ingredient.
DRUGIron
Subjects will receive supplemental iron therapy if ferritin is \<=100 ng/mL and TSAT is \<=20%. The investigator (or subinvestigator) will choose the route of administration and dose of prescription iron.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hgb at Week 4 | Baseline and Week 4 | Blood samples were collected from participants for measurement of Hgb values. The Baseline value was the latest pre-dose assessment. Change from Baseline at Week 4 was calculated by subtracting Baseline value from the post-dose visit value. The analysis was performed on All Treated Subjects Population which comprised of all participants who received at least one dose of GSK1278863. |
| Number of Participants by Hgb Change From Baseline Category at Week 4 | Baseline and Week 4 | Blood samples were collected from participants for measurement of Hgb values. The Baseline value was the latest pre-dose assessment. Change from Baseline at Week 4 was calculated by subtracting Baseline value from the post-dose visit value. The change in Hgb at Week 4 was classified into different categories (i.e., \<=-2.0, \>-2.0 to -1.0, \>-1.0 to 0, \>0 to 1.0, \>1.0 to 2.0, and \>2 g/dL), and the number of participants in each category were summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants with Hgb withinthe target range (10.0 to 12.0 g/dL) at each assessment visit was summarized. |
| Time to Reach the Lower Target Hgb Level (10.0 g/dL) | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. Participants who could not reach lower target were regarded as censored. The time (in days) to reach the lower target Hgb level (10.0 g/dL) was summarized using 25th percentile (P25), median, and 75th percentile (P75) by Kaplan-Meier method. |
| Number of Participants Who Had Hgb Level of Less Than 7.5 g/dL | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants who had Hgb level of less than 7.5 g/dL were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included. |
| Number of Participants Who Had Hgb Increase of More Than 2 g/dL Over Any 4 Weeks | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants who had Hgb increase of more than 2.0 g/dL over any 4 weeks were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included. |
| Number of Participants Who Had Hgb Level of More Than 13.0 g/dL | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants who had Hgb level of more than 13.0 g/dL were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included. |
| Number of Episodes of Achieving Hgb Level of More Than 13.0 g/dL | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of episodes in participants who had Hgb level of more than 13.0 g/dL were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included. |
| Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | 1, 2, 3 and 4 hours post dose at Weeks 12 and 24 | Blood samples were collected to evaluate AUC (0-4) at 1, 2, 3 and 4 hours post dose at Weeks 12 and 24. Pharmacokinetic (PK) parameters were calculated by standard non-compartmental analysis. PK Population consisted of all participants who received GSK1278863 with the PK samples collected and analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indiates data was not available. Geometric coefficient of variation could not be calculated when number of participant was equal to 1. |
| Maximum Observed Concentration (Cmax) of GSK1278863 | 1, 2, 3 and 4 hours post dose at Weeks 12 and 24 | Blood samples were collected to evaluate Cmax at 1, 2, 3 and 4 hours post dose at Weeks 12 and 24. PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indiates data was not available. Geometric coefficient of variation could not be calculated when number of participant was equal to 1. |
| Monthly Average Dose of Intravenous (IV) Iron During the Treatment Period | Up to Week 24 | Records of on-therapy iron medication were used to calculate average quarterly IV iron dose. Quarter 1 = (Randomization Date - Treatment Start Date at Week 12 - 1 \[day\]). Quarter 2 = (Treatment Start Date at Week 12 - Study Treatment Stop Date). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). |
| Hgb Values at the Indicated Time Points | Up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. |
| Change From Baseline in Ferritin | Baseline and up to Week 24 | Blood samples were collected from participants for measurement of serum ferritin at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. |
| Percent Change From Baseline in TSAT | Baseline and up to Week 24 | Blood samples were collected from participants for measurement of TSAT at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100\*(exponential \[mean change on log scale\]-1). |
| Percent Change From Baseline in Hepcidin | Baseline and up to Week 24 | Blood samples were collected from participants for measurement of hepcidin at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100\*(exponential \[mean change on log scale\]-1). If a laboratory value had a non-detectable level reported in the database, where the numeric value was missing, the value was not included in a summary. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). |
| Change From Baseline in Serum Iron | Baseline and up to Week 24 | Blood samples were collected from participants for measurement of serum iron at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. |
| Change From Baseline in Total Iron Binding Capacity (TIBC) | Baseline and up to Week 24 | Blood samples were collected from participants for measurement of TIBC at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. |
| Dose Level of GSK1278863 at Indicated Time Points | Up to Week 24 | Dose adjustment algorithm was used which was based on Hgb values at scheduled visits. Hgb values measured at unscheduled visits were not included. Mean dose during Week 12 to 24 is the average of dose at Weeks 12, 16, and 20. |
| Number of Participants With Frequency of Dose Adjustments | Up to Week 24 | Dose adjustment algorithm was used which was based on Hgb values at scheduled visits. Hgb values measured at unscheduled visits were not included. For dose adjustments frequency, the number of participants were provided by the number of dose adjustments (i.e. zero, one, two, three, four, and five or more). |
| Duration of Treatment Interruption Due to Hgb >13 g/dL | Up to Week 24 | Hgb values were used for making decision of treatment interruption. On-therapy Hgb values observed in both scheduled and unscheduled visits were counted. Participants who have no treatment interruption due to Hgb \>13.0 g/dL are not included |
| Number of Participants Who Used Iron During the Treatment Period | Up to Week 24 | The number of participants who used iron (both IV and oral iron) during the treatment period were summarized. |
| Change From Baseline in Hgb at the Indicated Time Points | Baseline and up to Week 24 | Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The Baseline value was the latest pre-dose assessment. Change from Baseline at indicated time-points was calculated by subtracting Baseline value from the post-dose visit value. |
Countries
Japan
Participant flow
Recruitment details
This was a 24-week, Phase 3, open-label, non-comparative, multicenter study to evaluate the efficacy and safety of GSK1278863 in Japanese hemodialysis participants with renal anemia not using Erythropoiesis Stimulating Agents. The study was conducted at 18 centers in Japan from 08-Aug-2016 to 17-Oct-2017.
Pre-assignment details
A total of 36 participants were screened and 8 failed screening because of not meeting eligibility criteria (7) and withdrawal by participants (1). The remaining 28 participants were enrolled in this study. This study consisted of a 4-week screening period, a 24-week treatment period and a 2 to 4-week follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants with newly started dialysis (dialysis newly started \<12 weeks before screening) or with maintenance dialysis (dialysis started \>=12 weeks before screening) received GSK1278863 orally once daily initially at 4 mg for 4 weeks from Day 1. Subsequently, participants received GSK1278863 orally once a day according to a pre-defined study treatment dose adjustment algorithm to achieve or maintain Hgb within the target range (10.0-12.0 g/dL). In participants taking oral iron before the study, their iron dose was not changed during the fixed-dose period. Supplemental iron therapy was administered if ferritin is \<=100 ng/mL and TSAT is \<=20%. | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 62.5 Years STANDARD_DEVIATION 10.16 |
| Dialysis Status Maintenance dialysis | 17 Participants |
| Dialysis Status Newly started dialysis | 11 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 28 Count of Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 12 / 28 |
| serious Total, serious adverse events | 3 / 28 |
Outcome results
Primary
Change From Baseline in Hgb at Week 4
Blood samples were collected from participants for measurement of Hgb values. The Baseline value was the latest pre-dose assessment. Change from Baseline at Week 4 was calculated by subtracting Baseline value from the post-dose visit value. The analysis was performed on All Treated Subjects Population which comprised of all participants who received at least one dose of GSK1278863.
Time frame: Baseline and Week 4
Population: All Treated Subjects Population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Change From Baseline in Hgb at Week 4 | 0.79 G/dL |
Primary
Number of Participants by Hgb Change From Baseline Category at Week 4
Blood samples were collected from participants for measurement of Hgb values. The Baseline value was the latest pre-dose assessment. Change from Baseline at Week 4 was calculated by subtracting Baseline value from the post-dose visit value. The change in Hgb at Week 4 was classified into different categories (i.e., \<=-2.0, \>-2.0 to -1.0, \>-1.0 to 0, \>0 to 1.0, \>1.0 to 2.0, and \>2 g/dL), and the number of participants in each category were summarized.
Time frame: Baseline and Week 4
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Number of Participants by Hgb Change From Baseline Category at Week 4 | <= -2.0 | 0 Participants |
| All Participants | Number of Participants by Hgb Change From Baseline Category at Week 4 | > -2.0 to -1.0 | 0 Participants |
| All Participants | Number of Participants by Hgb Change From Baseline Category at Week 4 | > -1.0 to 0 | 4 Participants |
| All Participants | Number of Participants by Hgb Change From Baseline Category at Week 4 | > 0 to 1.0 | 13 Participants |
| All Participants | Number of Participants by Hgb Change From Baseline Category at Week 4 | > 1.0 to 2.0 | 11 Participants |
| All Participants | Number of Participants by Hgb Change From Baseline Category at Week 4 | > 2.0 | 0 Participants |
Secondary
Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863
Blood samples were collected to evaluate AUC (0-4) at 1, 2, 3 and 4 hours post dose at Weeks 12 and 24. Pharmacokinetic (PK) parameters were calculated by standard non-compartmental analysis. PK Population consisted of all participants who received GSK1278863 with the PK samples collected and analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indiates data was not available. Geometric coefficient of variation could not be calculated when number of participant was equal to 1.
Time frame: 1, 2, 3 and 4 hours post dose at Weeks 12 and 24
Population: PK Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 43.3100 Hour*nanogram per milliliter (h*ng/mL) | — |
| All Participants | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 43.3100 Hour*nanogram per milliliter (h*ng/mL) | — |
| GSK1278863 2 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 30.9164 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 225.3 |
| GSK1278863 2 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 12, n=0,4,14,8,1,0,0 | 25.7228 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 289.9 |
| GSK1278863 2 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 33.8941 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 230.9 |
| GSK1278863 4 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 12, n=0,4,14,8,1,0,0 | 95.1319 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 111.9 |
| GSK1278863 4 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 86.3702 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 58.9 |
| GSK1278863 4 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 91.8474 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 91.1 |
| GSK1278863 6 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 133.3020 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 50.9 |
| GSK1278863 6 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 12, n=0,4,14,8,1,0,0 | 200.6036 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 62.9 |
| GSK1278863 6 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 171.4229 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 60.8 |
| GSK1278863 8 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 354.6083 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40 |
| GSK1278863 8 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 437.0983 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 18.7 |
| GSK1278863 8 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 12, n=0,4,14,8,1,0,0 | 233.3933 Hour*nanogram per milliliter (h*ng/mL) | — |
| GSK1278863 12 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 749.4583 Hour*nanogram per milliliter (h*ng/mL) | — |
| GSK1278863 12 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 749.4583 Hour*nanogram per milliliter (h*ng/mL) | — |
| GSK1278863 18 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), All, n=1,12,22,13,3,1,1 | 126.2883 Hour*nanogram per milliliter (h*ng/mL) | — |
| GSK1278863 18 mg | Area Under the Concentration-time Curve (AUC) From Time Zero to 4 Hours (AUC [0-4]) of GSK1278863 | AUC (0-4), Week 24, n=1,8,8,5,2,1,1 | 126.2883 Hour*nanogram per milliliter (h*ng/mL) | — |
Secondary
Change From Baseline in Ferritin
Blood samples were collected from participants for measurement of serum ferritin at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time frame: Baseline and up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Change From Baseline in Ferritin | Week 4 | -80.11 Microgram per liter (µg/L) | Standard Deviation 51.826 |
| All Participants | Change From Baseline in Ferritin | Week 12 | -126.29 Microgram per liter (µg/L) | Standard Deviation 120.382 |
| All Participants | Change From Baseline in Ferritin | Week 24 | -107.03 Microgram per liter (µg/L) | Standard Deviation 143.048 |
Secondary
Change From Baseline in Hgb at the Indicated Time Points
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The Baseline value was the latest pre-dose assessment. Change from Baseline at indicated time-points was calculated by subtracting Baseline value from the post-dose visit value.
Time frame: Baseline and up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Change From Baseline in Hgb at the Indicated Time Points | Week 4 | 0.79 G/dL | Standard Deviation 0.673 |
| All Participants | Change From Baseline in Hgb at the Indicated Time Points | Week 8 | 1.66 G/dL | Standard Deviation 0.773 |
| All Participants | Change From Baseline in Hgb at the Indicated Time Points | Week 12 | 1.98 G/dL | Standard Deviation 0.984 |
| All Participants | Change From Baseline in Hgb at the Indicated Time Points | Week 16 | 2.28 G/dL | Standard Deviation 1.248 |
| All Participants | Change From Baseline in Hgb at the Indicated Time Points | Week 20 | 2.24 G/dL | Standard Deviation 1.174 |
| All Participants | Change From Baseline in Hgb at the Indicated Time Points | Week 24 | 2.01 G/dL | Standard Deviation 1.121 |
Secondary
Change From Baseline in Serum Iron
Blood samples were collected from participants for measurement of serum iron at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time frame: Baseline and up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Change From Baseline in Serum Iron | Week 4 | -0.8123 Micromoles per liter (µmol/L) | Standard Deviation 4.92624 |
| All Participants | Change From Baseline in Serum Iron | Week 12 | 2.0916 Micromoles per liter (µmol/L) | Standard Deviation 10.74722 |
| All Participants | Change From Baseline in Serum Iron | Week 24 | 1.4584 Micromoles per liter (µmol/L) | Standard Deviation 7.72121 |
Secondary
Change From Baseline in Total Iron Binding Capacity (TIBC)
Blood samples were collected from participants for measurement of TIBC at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time frame: Baseline and up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Change From Baseline in Total Iron Binding Capacity (TIBC) | Week 4 | 8.5904 umol/L | Standard Deviation 4.93732 |
| All Participants | Change From Baseline in Total Iron Binding Capacity (TIBC) | Week 12 | 10.8611 umol/L | Standard Deviation 6.32355 |
| All Participants | Change From Baseline in Total Iron Binding Capacity (TIBC) | Week 24 | 9.3388 umol/L | Standard Deviation 9.92131 |
Secondary
Dose Level of GSK1278863 at Indicated Time Points
Dose adjustment algorithm was used which was based on Hgb values at scheduled visits. Hgb values measured at unscheduled visits were not included. Mean dose during Week 12 to 24 is the average of dose at Weeks 12, 16, and 20.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Day 1 | 4.0 mg |
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Week 4 | 4.0 mg |
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Week 8 | 4.0 mg |
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Week 12 | 4.0 mg |
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Week 16 | 4.0 mg |
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Week 20 | 4.0 mg |
| All Participants | Dose Level of GSK1278863 at Indicated Time Points | Week 12 to 24 | 4.00 mg |
Secondary
Duration of Treatment Interruption Due to Hgb >13 g/dL
Hgb values were used for making decision of treatment interruption. On-therapy Hgb values observed in both scheduled and unscheduled visits were counted. Participants who have no treatment interruption due to Hgb \>13.0 g/dL are not included
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Duration of Treatment Interruption Due to Hgb >13 g/dL | 84 Days |
Secondary
Hgb Values at the Indicated Time Points
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Hgb Values at the Indicated Time Points | Day 1 | 9.10 G/dL | Standard Deviation 0.696 |
| All Participants | Hgb Values at the Indicated Time Points | Week 4 | 9.90 G/dL | Standard Deviation 0.907 |
| All Participants | Hgb Values at the Indicated Time Points | Week 8 | 10.76 G/dL | Standard Deviation 0.957 |
| All Participants | Hgb Values at the Indicated Time Points | Week 12 | 11.09 G/dL | Standard Deviation 1.117 |
| All Participants | Hgb Values at the Indicated Time Points | Week 16 | 11.38 G/dL | Standard Deviation 1.286 |
| All Participants | Hgb Values at the Indicated Time Points | Week 20 | 11.34 G/dL | Standard Deviation 1.169 |
| All Participants | Hgb Values at the Indicated Time Points | Week 24 | 11.12 G/dL | Standard Deviation 1.21 |
Secondary
Maximum Observed Concentration (Cmax) of GSK1278863
Blood samples were collected to evaluate Cmax at 1, 2, 3 and 4 hours post dose at Weeks 12 and 24. PK parameters were calculated by standard non-compartmental analysis. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indiates data was not available. Geometric coefficient of variation could not be calculated when number of participant was equal to 1.
Time frame: 1, 2, 3 and 4 hours post dose at Weeks 12 and 24
Population: PK Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 27.5000 ng/mL | — |
| All Participants | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 27.5000 ng/mL | — |
| GSK1278863 2 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 16.7474 ng/mL | Geometric Coefficient of Variation 217.4 |
| GSK1278863 2 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 12, n=0,4,14,8,1,0,0 | 13.9578 ng/mL | Geometric Coefficient of Variation 340.6 |
| GSK1278863 2 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 18.3448 ng/mL | Geometric Coefficient of Variation 202.3 |
| GSK1278863 4 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 12, n=0,4,14,8,1,0,0 | 57.6572 ng/mL | Geometric Coefficient of Variation 81.2 |
| GSK1278863 4 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 44.8853 ng/mL | Geometric Coefficient of Variation 49.8 |
| GSK1278863 4 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 52.6391 ng/mL | Geometric Coefficient of Variation 70.4 |
| GSK1278863 6 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 100.2261 ng/mL | Geometric Coefficient of Variation 41.3 |
| GSK1278863 6 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 12, n=0,4,14,8,1,0,0 | 122.9883 ng/mL | Geometric Coefficient of Variation 56.9 |
| GSK1278863 6 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 113.6784 ng/mL | Geometric Coefficient of Variation 50.4 |
| GSK1278863 8 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 194.6229 ng/mL | Geometric Coefficient of Variation 7.7 |
| GSK1278863 8 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 202.9384 ng/mL | Geometric Coefficient of Variation 3.5 |
| GSK1278863 8 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 12, n=0,4,14,8,1,0,0 | 179.0000 ng/mL | — |
| GSK1278863 12 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 311.0000 ng/mL | — |
| GSK1278863 12 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 311.0000 ng/mL | — |
| GSK1278863 18 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, All, n=1,12,22,13,3,1,1 | 93.4000 ng/mL | — |
| GSK1278863 18 mg | Maximum Observed Concentration (Cmax) of GSK1278863 | Cmax, Week 24, n=1,8,8,5,2,1,1 | 93.4000 ng/mL | — |
Secondary
Monthly Average Dose of Intravenous (IV) Iron During the Treatment Period
Records of on-therapy iron medication were used to calculate average quarterly IV iron dose. Quarter 1 = (Randomization Date - Treatment Start Date at Week 12 - 1 \[day\]). Quarter 2 = (Treatment Start Date at Week 12 - Study Treatment Stop Date). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Monthly Average Dose of Intravenous (IV) Iron During the Treatment Period | Quarter 1; n= 3 | 231.61 Mg | Standard Deviation 99.916 |
| All Participants | Monthly Average Dose of Intravenous (IV) Iron During the Treatment Period | Quarter 2; n= 4 | 217.19 Mg | Standard Deviation 86.529 |
Secondary
Number of Episodes of Achieving Hgb Level of More Than 13.0 g/dL
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of episodes in participants who had Hgb level of more than 13.0 g/dL were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Number of Episodes of Achieving Hgb Level of More Than 13.0 g/dL | 7 Episodes |
Secondary
Number of Participants Who Had Hgb Increase of More Than 2 g/dL Over Any 4 Weeks
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants who had Hgb increase of more than 2.0 g/dL over any 4 weeks were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Who Had Hgb Increase of More Than 2 g/dL Over Any 4 Weeks | 1 Participants |
Secondary
Number of Participants Who Had Hgb Level of Less Than 7.5 g/dL
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants who had Hgb level of less than 7.5 g/dL were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Who Had Hgb Level of Less Than 7.5 g/dL | 0 Participants |
Secondary
Number of Participants Who Had Hgb Level of More Than 13.0 g/dL
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants who had Hgb level of more than 13.0 g/dL were summarized. On-therapy Hgb values observed in both scheduled and unscheduled visits were included.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Participants | Number of Participants Who Had Hgb Level of More Than 13.0 g/dL | 3 Participants |
Secondary
Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL)
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. The number of participants with Hgb withinthe target range (10.0 to 12.0 g/dL) at each assessment visit was summarized.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Week 4, within range | 13 Participants |
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Week 8, within range | 20 Participants |
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Day 1, within range | 3 Participants |
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Week 12, within range | 18 Participants |
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Week 16, within range | 17 Participants |
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Week 20, within range | 20 Participants |
| All Participants | Number of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) | Week 24, within range | 23 Participants |
Secondary
Number of Participants Who Used Iron During the Treatment Period
The number of participants who used iron (both IV and oral iron) during the treatment period were summarized.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Number of Participants Who Used Iron During the Treatment Period | Oral iron | 9 Participants |
| All Participants | Number of Participants Who Used Iron During the Treatment Period | Intravenous iron | 4 Participants |
| All Participants | Number of Participants Who Used Iron During the Treatment Period | Any iron medication | 12 Participants |
Secondary
Number of Participants With Frequency of Dose Adjustments
Dose adjustment algorithm was used which was based on Hgb values at scheduled visits. Hgb values measured at unscheduled visits were not included. For dose adjustments frequency, the number of participants were provided by the number of dose adjustments (i.e. zero, one, two, three, four, and five or more).
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Participants | Number of Participants With Frequency of Dose Adjustments | Number of dose adjustments=1 | 9 Participants |
| All Participants | Number of Participants With Frequency of Dose Adjustments | Number of dose adjustments=2 | 7 Participants |
| All Participants | Number of Participants With Frequency of Dose Adjustments | Any dose adjustments | 21 Participants |
| All Participants | Number of Participants With Frequency of Dose Adjustments | Number of dose adjustments=0 | 7 Participants |
| All Participants | Number of Participants With Frequency of Dose Adjustments | Number of dose adjustments=3 | 4 Participants |
| All Participants | Number of Participants With Frequency of Dose Adjustments | Number of dose adjustments=4 | 1 Participants |
| All Participants | Number of Participants With Frequency of Dose Adjustments | Number of dose adjustments=5 or more | 0 Participants |
Secondary
Percent Change From Baseline in Hepcidin
Blood samples were collected from participants for measurement of hepcidin at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100\*(exponential \[mean change on log scale\]-1). If a laboratory value had a non-detectable level reported in the database, where the numeric value was missing, the value was not included in a summary. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time frame: Baseline and up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Participants | Percent Change From Baseline in Hepcidin | Week 4, n=26 | -64.78 Percentage of hepcidin |
| All Participants | Percent Change From Baseline in Hepcidin | Week 12, n=22 | -61.74 Percentage of hepcidin |
| All Participants | Percent Change From Baseline in Hepcidin | Week 24, n=21 | -55.67 Percentage of hepcidin |
Secondary
Percent Change From Baseline in TSAT
Blood samples were collected from participants for measurement of TSAT at indicated time points. The Baseline value was the latest pre-dose assessment. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Percent change from Baseline was calculated as 100\*(exponential \[mean change on log scale\]-1).
Time frame: Baseline and up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Participants | Percent Change From Baseline in TSAT | Week 4 | -23.06 Percentage of transferrin |
| All Participants | Percent Change From Baseline in TSAT | Week 12 | -15.31 Percentage of transferrin |
| All Participants | Percent Change From Baseline in TSAT | Week 24 | -10.07 Percentage of transferrin |
Secondary
Time to Reach the Lower Target Hgb Level (10.0 g/dL)
Blood samples were collected from participants for measurement of Hgb values at indicated time points. Hgb was evaluated using Hgb analyzer. Participants who could not reach lower target were regarded as censored. The time (in days) to reach the lower target Hgb level (10.0 g/dL) was summarized using 25th percentile (P25), median, and 75th percentile (P75) by Kaplan-Meier method.
Time frame: Up to Week 24
Population: All Treated Subjects Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Reach the Lower Target Hgb Level (10.0 g/dL) | 57.0 Days |