Study to Assess the Pharmacokinetics of GSK1278863 in Sub... | NCT02243306

NCT02243306

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2014-001197-34	EudraCT Number

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1	Experimental	Subjects on continuous ambulatory peritoneal dialysis (CAPD) will receive 5 mg of GSK1278863 orally, once daily for 14 days.	Drug: GSK1278863
Cohort 2	Experimental	Subjects on automated peritoneal dialysis (APD) will receive 5 mg of GSK1278863 orally, once daily for 14 days	Drug: GSK1278863

Name	Type	Description	Arm Group Labels	Other Names
GSK1278863	Drug	Round, biconvex, white film coated tablet containing 5 mg GSK1278863.	Cohort 1 Cohort 2

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Area Under the Concentration-time Curve (AUC) Over the Dosing Interval (AUC[0-tau]) of GSK1278863 and Its Metabolites	Serial blood samples were collected from participants at indicated time points for Pharmacokinetic (PK) analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. PK Population comprised of participants in the 'All Subjects' Population for whom a PK sample was obtained and analyzed.	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1; Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours post-dose on Day 14
AUC From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-inf]) of GSK1278863 and Its Metabolites	Serial blood samples were collected from participants at indicated time points for PK analysis of GSK1278863 and its metabolites (GSK2487818 and GSK2531398). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants.	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
Maximum Observed Concentration (Cmax) of GSK1278863 and Its Metabolites	Serial blood samples were collected from participants at indicated time points for PK analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1; Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours post-dose on Day 14

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)	An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/birth defect, other situations, and is associated with liver injury and impaired liver function. Analysis was performed on All Subjects Population which comprised of all enrolled participants who received at least one dose of study treatment.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

SAFETY:

Satisfactory medical evaluation based upon medical history, medication history, physical examination, and clinical laboratory data obtained at the Screening visit. The determination of clinical significance will be made by the Investigator and the GlaxoSmithKline (GSK) Medical Monitor and will require that the finding is unlikely to introduce additional risk factors or interfere with the study procedures, or the integrity of the study.
Corrected QT interval (QTc) <470 milliseconds (msec) OR QTc <480 msec in subjects with Bundle Branch Block. These should be based on average of triplicate values obtained over a brief recording period at Screening and on Day -1 and the single reading on Day 17. The same QT correction formula should be used to determine inclusion and discontinuation for any individual subject throughout the study.
Vitamin B12 and folate above the lower limit of normal at Screening.
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), and bilirubin <=1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

EFFICACY:

A subject is eligible to enroll and participate in this study if he/she has ESRD and is on peritoneal dialysis for at least 2 months with an average urine output of <750 mL/daily with a combined weekly (urine and peritoneal dialysis output) Kt/V urea >1.7 measured at any time within last 3 months.
No history of peritoneal dialysis-associated peritonitis, peritoneal catheter tunnel (exit site) infection or leakage for at least 3 months before study.
Meets the following erythropoiesis stimulating agent (ESA) criteria: Is ESA naive (i.e., no ESA use within the previous 12 weeks of screening) OR agrees to discontinue ESA (if currently using ESA) for at least 7 days prior to first dose of GSK1278863 until completion of Follow-up visit (If the subject has a scheduled ESA interval which is <=7 days, ESA treatment must be discontinued for at least 7 days prior to first dose of GSK1278863. If the subject has a scheduled ESA interval which is >7 days, ESA treatment must be discontinued for at least the scheduled interval length [e.g., if ESA interval is 14 days, then ESA must be discontinued for >=14 days] prior to the first dose of GSK1278863)
Has a haemoglobin value: For ESA naïve subjects: <10.0 g/dL (UK site(s) only: <=11.0 g/dL); For subjects receiving ongoing ESA treatment: <=11.0 g/dL at Screening (UK site(s) only: <=12.0 g/dL at Screening).

OTHER:

Subjects who are >=18 years of age at the time of Screening.
A female subject is eligible to participate if she is of: (a) Childbearing potential, and agrees to use one of the contraception methods described in the protocol. This criterion must be followed from the time of Screening until completion of the Follow-up Visit; (b) Non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (In questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 international units (IU)/litre (L) and estradiol <=10 picograms (pg)/mL (or <=37 picomoles [pmol]/L) is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described in the protocol 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. For most forms of HRT, at least 2 months must elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
Body weight >45 kilograms (kg) and <140 kg at Screening.
The subject is mentally and legally able to comply with the requirements and restrictions of the protocol and has provided signed informed consent prior to participation in any protocol-specific procedures, including Screening procedures.

Exclusion Criteria:

SAFETY

A positive test for Human Immunodeficiency Virus (HIV) antibody.
Uncontrolled hypertension (diastolic blood pressure [BP] >100 millimetres of mercury [mmHg] or systolic BP >170 mmHg) at Screening.
History of drug abuse or dependence within 6 months of the study.
History of sensitivity to GSK1278863, or its components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
History of thrombosis defined as deep vein thrombosis, stroke, pulmonary embolism or other thrombosis related condition within 3 months prior to Screening.
History of myocardial infarction or acute coronary syndrome within 3 months prior to Screening.
History of stroke or transient ischaemic attack within 3 months prior to Screening.
Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of GSK1278863. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, or celiac sprue. Examples of conditions that could interfere with hepatic function include Gilbert's syndrome.
Evidence of active peptic, duodenal or esophageal ulcer disease at Screening OR history of clinically significant gastro-intestinal (GI) bleeding within 3 months prior to Screening.
Subjects with chronic inflammatory disease that could impact erythropoiesis (e.g. scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).
Subjects with a history of symptomatic right heart failure.
Subjects with Class III or Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
Active malignancy or diagnosis of malignancy within 5 years prior to Screening (excluding successfully treated basal or squamous cell carcinoma).
History of proliferative vascular eye disease (e.g., choroidal or retinal disease, such as neovascular age-related macular degeneration, proliferative diabetic retinopathy or macular edema) based upon having had an ophthalmologic exam within 12 months prior to the end of the Screening period (The screening period is from the screening visit until Day -1).
Pregnant females as determined by positive serum human chorionic gonadotropin (hCG) test at Screening or Day -1.
Lactating females.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period prior to first dose.
Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, broccoli, green beans, or apples from 7 days prior to the first dose of investigational product until the Follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor this will not interfere with the study procedures and compromise subject safety.
Use or planned use of any prescription or non-prescription drugs that are prohibited within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of GSK1278863 until completion of the follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
The following medications are specifically prohibited for the duration of the study (from Screening to the follow-up visit at the end of the study): Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of low dose (<=325 mg/day) aspirin/acetylsalicylic acid. Occasional NSAID use is permitted; Immunosuppressant drugs and drugs used to treat malignancies (including corticosteroids at doses >10 mg prednisolone per day or equivalent) within 2 weeks of first dose of GSK1278863. Note: Failed transplant subjects back on peritoneal dialysis are eligible for participating in this study but should not be on immunosuppressive medications within 3 months prior to Screening.
The subject has participated in a clinical trial and has received an experimental investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

EFFICACY:

The values of ferritin and transferrin within 3 months prior to Screening are: (a) transferrin saturation <20%; (b) serum ferritin <100 micrograms (mcg)/L

OTHER:

A positive pre-dosing drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. A positive pre-dosing screen for medications that are prescribed to a renal subject for pre-existing condition(s), may be allowed if in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
History of regular use within 6 months of the study of tobacco- or nicotine-containing products in excess of 20 cigarettes per day or equivalent.
Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the informed consent and as directed by site staff.
Subject is either an immediate family member of a participating Investigator, study coordinator, employee of an Investigator; or is a member of the staff conducting the study.

Contacts/Locations Module

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Lakewood	Colorado	80228	United States
GSK Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
31583094	Background	Caltabiano S, Cizman B, Burns O, Mahar KM, Johnson BM, Ramanjineyulu B, Serbest G, Cobitz AR. Effect of renal function and dialysis modality on daprodustat and predominant metabolite exposure. Clin Kidney J. 2019 Feb 18;12(5):693-701. doi: 10.1093/ckj/sfz013. eCollection 2019 Oct.

IPD Sharing Statement Module

No data available

No data is available for this block.

A total of 20 participants with ESRD were screened; of which 12 were screen failures and 8 entered the study to receive 5 milligrams (mg) of GSK1278863 once daily for 14 days.

Arm/Group Information

ID	Title	Description
FG000	Participants Undergoing CAPD	Participants on CAPD received 1 tablet (5 mg) of GSK1278863 by oral route once daily with half glass of water for 14 days. On Day 1 and Day 14, the dose was administered within 30 minutes after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid; on any other study days, the dose was administered within 2 hours after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid.
FG001	Participants Undergoing APD	Participants on APD received 1 tablet (5 mg) of GSK1278863 by oral route once daily with half glass of water for 14 days. On Day 1 and Day 14, the dose was administered within 30 minutes after completion of night APD treatment or morning last fill of peritoneal dialysis fluid; on any other study days, the dose was administered within 2 hours after completion of night APD treatment or morning last fill of peritoneal dialysis fluid.

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG0001 subjects FG0017 subjects
COMPLETED		FG0001 subjects FG0014 subjects
NOT COMPLETED		FG0000 subjects FG0013 subjects

Type	Comment	Reasons
Adverse Event		FG0000 subjects FG0011 subjects
Other: Reached stopping criteria		FG0000 subjects FG001

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Participants Undergoing CAPD	Participants on CAPD received 1 tablet (5 mg) of GSK1278863 by oral route once daily with half glass of water for 14 days. On Day 1 and Day14, the dose was administered within 30 minutes after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid; on any other study days, the dose was administered within 2 hours after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous	Age is calculated based on screening date, using date of birth, truncated to integer value.

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Area Under the Concentration-time Curve (AUC) Over the Dosing Interval (AUC[0-tau]) of GSK1278863 and Its Metabolites

Serial blood samples were collected from participants at indicated time points for Pharmacokinetic (PK) analysis of GSK1278863 and its metabolites (GSK2391220, GSK2487818, GSK2506102, GSK2531398, GSK2531403 and GSK2531401). Geometric mean and geometric coefficient of variation has been presented for all metabolites. NA indicates data is not available. Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants. PK Population comprised of participants in the 'All Subjects' Population for whom a PK sample was obtained and analyzed.

PK Population. Only those participants available at the specified time points were analyzed (represented by n=x in category titles).

Posted

Geometric Mean

Geometric Coefficient of Variation

Hour into nanograms per milliliter

Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1; Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72 hours post-dose on Day 14

ID	Title	Description

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Participants Undergoing CAPD	Participants on CAPD received 1 tablet (5 mg) of GSK1278863 by oral route once daily with half glass of water for 14 days. On Day 1 and Day14, the dose was administered within 30 minutes after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid; on any other study days, the dose was administered within 2 hours after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 20.1	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
GSK Response Center	GlaxoSmithKline	866-435-7343		GSKClinicalSupportHD@gsk.com

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 20, 2016	Mar 22, 2018	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Sep 14, 2017	Mar 22, 2018	SAP_001.pdf

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

ID	Term
D000740	Anemia
D051436	Renal Insufficiency, Chronic

ID	Term
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D051437	Renal Insufficiency
D007674	Kidney Diseases

Intervention Browse Module

ID	Term
C000599718	GSK1278863

Masking Info

EG0001 events1 affected1 at risk

EG0011 events1 affected7 at risk

Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants.

Standard deviation could not be calculated for CAPD cohort due to small number of participants.

OG001-0.00165± 0.044431

Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants.

OG0011.00(1.0 to 3.0)

Title	Measurements
	OG0001.019(0.944 to 1.100)

Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants

Geometric coefficient of variation could not be calculated for CAPD cohort due to small number of participants.

OG000	Participants Undergoing CAPD	Participants on CAPD received 1 tablet (5 mg) of GSK1278863 by oral route once daily with half glass of water for 14 days. On Day 1 and Day14, the dose was administered within 30 minutes after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid; on any other study days, the dose was administered within 2 hours after completion of night CAPD treatment or morning last fill of peritoneal dialysis fluid.
OG001	Participants Undergoing APD	Participants on APD received 1 tablet (5 mg) of GSK1278863 by oral route once daily with half glass of water for 14 days. On Day 1 and Day14, the dose was administered within 30 minutes after completion of night APD treatment or morning last fill of peritoneal dialysis fluid; on any other study days, the dose was administered within 2 hours after completion of night APD treatment or morning last fill of peritoneal dialysis fluid.