Study to Assess the Pharmacokinetics of GSK1278863 in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis
Condition: Anaemia
MeSH terms: Kidney Failure, Chronic
Intervention: GSK1278863
Intervention description: Round, biconvex, white film coated tablet containing 5 mg GSK1278863.
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: pharmacokinetics; Chronic kidney disease; peritoneal dialysis; hemoglobin; Anemia; GSK1278863; Prolyl hydroxylase inhibitor; erythropoiesis stimulating agents

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.