Clinical trial NCT02243306: Study to Assess the Pharmacokinetics of GSK1278863 in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis
Official title: A Repeat-Dose, Open-Label, Parallel-Group Study to Assess the Pharmacokinetics of GSK1278863 and Metabolites in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Anaemia
Keywords: pharmacokinetics
Chronic kidney disease
peritoneal dialysis
hemoglobin
Anemia
GSK1278863
Prolyl hydroxylase inhibitor
erythropoiesis stimulating agents
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-09-17
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: GSK1278863 is an orally-active, novel small molecule agent which inhibits hypoxia-inducible factor (HIF) prolyl -4- hydroxylases (PHDs) and is in development for the treatment of anaemia associated with chronic kidney disease (CKD). As the kidney represents a major site of elimination for many drugs and their metabolites, and GSK1278863 will be administered to subjects with various stages of renal disease, it is important to characterize the pharmacokinetics in this target patient population. The purpose of this study is to characterize the pharmacokinetics of GSK1278863 and its metabolites in subjects with end stage renal disease (ESRD) undergoing peritoneal dialysis. This will be a repeat-dose, open-label, parallel-group study. Approximately 30 subjects with ESRD will be enrolled in two cohorts (15 subjects in each cohort) to ensure that 6 subjects on continuous ambulatory peritoneal dialysis (CAPD) (cohort 1) and 6 subjects on automated peritoneal dialysis APD (cohort 2) complete dosing and critical assessments. GSK1278863 will be administered once daily for 14 days. Primary pharmacokinetic assessments will be made on Days 1 and 14.


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.

Primary outcomes:
measure: Area Under the Concentration-time Curve (AUC) Over the Dosing Interval (AUC[0-tau]) of GSK1278863 and Its Metabolites
timeFrame: 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
measure: AUC From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-inf]) of GSK1278863 and Its Metabolites
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post-dose on Day 1
measure: Maximum Observed Concentration (Cmax) of GSK1278863 and Its Metabolites
timeFrame: 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: Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)
timeFrame: Up to Day 24
measure: Change From Baseline in Glucose, Calcium, Chloride, Carbon-dioxide (CO2), Potassium, Sodium and Urea Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Albumin and Protein Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Direct Bilirubin, Bilirubin, Creatinine and Urate Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Gamma Glutamyl Aminotransferase (GGT) Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Alanine Aminotransferase (ALT) and Creatinine Kinase Levels
timeFrame: Baseline and Day 3, 7, 11, 14, 17
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Erythrocyte and Reticulocyte Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Hematocrit Levels
timeFrame: Baseline and Day 17
measure: Change From Baseline in Hemoglobin Levels
timeFrame: Baseline and Day 3, 7, 11, 17
measure: Change From Baseline in Mean Corpuscular Hemoglobin Concentration (MCHC)
timeFrame: Baseline and Day 17
measure: Change From Baseline in Mean Corpuscular Volume (MCV)
timeFrame: Baseline and Day 17
measure: Change From Baseline in Mean Corpuscular Hemoglobin (MCH) Levels
timeFrame: Baseline and Day 17
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Day 17
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline, Day 17 and Day 24
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline, Day 17 and Day 24
measure: Change From Baseline in Body Temperature
timeFrame: Baseline, Day 17 and Day 24
measure: Number of Participants With Abnormal Physical Examination Findings
timeFrame: Up to Day 17
measure: Peritoneal Dialysis Clearance of GSK1278863 and Metabolites
timeFrame: Day 14
measure: Terminal Phase Half-life (t 1/2) of GSK1278863 and Metabolites
timeFrame: 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
measure: Time of Occurrence of Cmax (Tmax) of GSK1278863 and Metabolites
timeFrame: 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
measure: Accumulation Ratio of GSK1278863 and Metabolites
timeFrame: Day 1 and Day 14
measure: Time Invariance Ratio of GSK1278863 and Metabolites
timeFrame: Day 1 and Day 14
measure: Plasma Concentration of Erythropoietin
timeFrame: Pre-dose and 4, 8 ,12, 24 hours post-dose on Day 1 and Day 14; Pre-dose on Day 3, 7, 11
measure: Plasma Concentration of Hepcidin
timeFrame: Pre-dose and 4, 8 ,12, 24 hours post-dose on Day 1 and Day 14; Pre-dose on Day 3, 7, 11
Other outcomes:
Locations:
city: Lakewood
country: United States
facility: GSK Investigational Site
state: Colorado
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.