Study to Assess the Pharmacokinetics of GSK1278863 in Subjects With End Stage Renal Disease Undergoing Peritoneal Dialysis

NCT02243306 | Completed Phase 1 Results

• 2 other identifiers: 2009422014-001197-34
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

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.

Conditions

Anaemia

Keywords

pharmacokinetics; Chronic kidney disease; peritoneal dialysis; hemoglobin; Anemia; GSK1278863; Prolyl hydroxylase inhibitor; erythropoiesis stimulating agents

Outcome Measures

Primary Outcomes (3)

• 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 (25)

• Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)

  Up to Day 24

• Change From Baseline in Glucose, Calcium, Chloride, Carbon-dioxide (CO2), Potassium, Sodium and Urea Levels

  Baseline and Day 17

• Change From Baseline in Albumin and Protein Levels

  Baseline and Day 17

• Change From Baseline in Direct Bilirubin, Bilirubin, Creatinine and Urate Levels

  Baseline and Day 17

• Change From Baseline in Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Gamma Glutamyl Aminotransferase (GGT) Levels

  Baseline and Day 17

Study Arms (2)

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

Interventions

GSK1278863 DRUG

Round, biconvex, white film coated tablet containing 5 mg GSK1278863.

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Lakewood, Colorado, 80228, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• 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.

  PMID: 31583094 BACKGROUND

MeSH Terms

Conditions

Anemia; Renal Insufficiency, Chronic

Interventions

GSK1278863

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 29, 2014
• First Posted: September 17, 2014
• Study Start: October 24, 2014
• Primary Completion: May 10, 2017
• Study Completion: May 10, 2017
• Last Updated: April 9, 2019
• Results First Posted: March 11, 2019

Record last verified: 2019-03

Locations

US (2)