A Phase I, Single-Dose, Randomized and Single-Blind (Part 1), Fixed Sequence and Open-Label (Part 2), Studyto Evaluate the Safety, Pharmacokinetics, andPharmacodynamics of 1278863A in Subjects With RenalImpairment and Matched Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- GSK1278863A
- Conditions
- Kidney Disease
- Sponsor
- GlaxoSmithKline
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- AUC (0-24), Cmax, tmax and half-life
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
The purpose of this study is to characterize the safety and tolerability of single doses of compound 1278863A in subjects with renal impairment.
Detailed Description
Compound 1278863A is a novel small molecule agent, which stimulates erythropoiesis through inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylases (EGLNs). This compound is being developed for the treatment of anemia. This study, PHI112843, will be the first administration of 1278863A to investigate the safety, tolerability, pharmacokinetics and/or pharmacodynamics of single oral doses of 50 mg and 150 mg in pre-dialysis subjects with moderate or severe renal impairment and 150 mg in hemodialysis-dependent subjects. Four to eight subjects will complete each dose cohort. Multiple blood samples for pharmacokinetic and/or pharmacodynamic analyses will be obtained post-dose in each cohort. Safety will be assessed by measurement of vital signs, cardiac monitoring, collection of adverse event assessments and laboratory safety tests.
Investigators
Eligibility Criteria
Inclusion Criteria
- •A male or female is eligible to enroll and participate in this study if he/she:
- •(Part 1) has Moderate to Severe Renal Impairment (equivalent to NKF KDOQI Stage 3 or 4, not receiving dialysis) as determined by estimated Glomerular Filtration Rate (eGFR) calculated by the abbreviated MDRD equation, OR has Normal Renal Function determined by creatinine clearance (CLCR) via the Cockcroft-Gault equation, using serum creatinine and demographic data, obtained at Screening. Subjects with Normal Renal Function should have no greater than trace blood or protein on Screening urinalysis.
- •(Part 2) has severe renal impairment (end-stage renal failure) and has been on stable hemodialysis treatment (three times weekly) for 3 months prior to Screening.
- •otherwise healthy or considered clinically stable with respect to underlying renal impairment as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
- •has clinical laboratory test results that are considered clinically stable in the opinion of the Principal Investigator, especially if the clinical abnormality or laboratory parameter is deemed associated with the subject's underlying renal impairment. A normal subject with a clinical abnormality or laboratory parameters outside the reference range may be included only if the Investigator and the Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- •Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- •A female subject is eligible to participate if she is of:
- •Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\]. 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 2-4 weeks will 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.
- •Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study drug until completion of the Follow-up visit.
Exclusion Criteria
- •A hemoglobin value at Screening is:
- •Healthy male subjects or post-menopausal females: \> 16.5 g/dL
- •Healthy female subjects: \> 15.5 g/dL
- •Renally impaired male or female subjects: \<10 g/dL
- •The values of hematological parameters at Screening, for healthy subjects only, are outside the reference range and clinically significant deemed by the Investigator and Medical Monitor
- •The values of the following tests at Screening, for healthy subjects only, are:
- •TIBC: outside the reference range
- •Serum iron: outside the reference range
- •Serum ferritin: outside the reference range
- •Clinically significant abnormal CPK determined by the Investigator and Medical Monitor.
Arms & Interventions
Subjects with renal impairment, non-dialysis
Subjects with moderate to severe renal impairment equivalent to National Kidney Foundation Kidney Disease Outcomes Quality Initiative stage 3 and stage 4 who are not undergoing dialysis will be included. Subjects will receive single 50 mg and 150 mg oral doses of GSK1278863A across two dosing periods in a single-blind, randomized sequence. Doses of GSK1278863A will be given as 25 mg and 100 mg tablets, with matching placebo tablets to maintain treatment blinding.
Intervention: GSK1278863A
Subjects with renal impairment, non-dialysis
Subjects with moderate to severe renal impairment equivalent to National Kidney Foundation Kidney Disease Outcomes Quality Initiative stage 3 and stage 4 who are not undergoing dialysis will be included. Subjects will receive single 50 mg and 150 mg oral doses of GSK1278863A across two dosing periods in a single-blind, randomized sequence. Doses of GSK1278863A will be given as 25 mg and 100 mg tablets, with matching placebo tablets to maintain treatment blinding.
Intervention: Placebo
Healthy volunteers
Healthy subjects will be matched to the moderate and severe renally impaired subjects for gender, age, and BMI. Subjects will receive single 50 mg and 150 mg oral doses of GSK1278863A across two dosing periods in a single-blind, randomized sequence. Doses of GSK1278863A will be given as 25 mg and 100 mg tablets, with matching placebo tablets to maintain treatment blinding.
Intervention: GSK1278863A
Healthy volunteers
Healthy subjects will be matched to the moderate and severe renally impaired subjects for gender, age, and BMI. Subjects will receive single 50 mg and 150 mg oral doses of GSK1278863A across two dosing periods in a single-blind, randomized sequence. Doses of GSK1278863A will be given as 25 mg and 100 mg tablets, with matching placebo tablets to maintain treatment blinding.
Intervention: Placebo
Hemodialysis dependent subjects
The arm will consist of subjects with severe renal impairment (end-stage renal failure) who have been on stable hemodialysis treatment scheduled three times per week. Subjects will receive single oral doses of 150 mg GSK1278863A in each of 2 dosing periods in an open-label, fixed sequence. GSK1278863A will be administered just prior to receiving scheduled hemodialysis in Dosing Period 1. In Dosing Period 2, subjects will receive a single oral dose of GSK1278863 the morning after completion of a scheduled hemodialysis session.
Intervention: GSK1278863A
Outcomes
Primary Outcomes
AUC (0-24), Cmax, tmax and half-life
Time Frame: Parts 1&2: Days 1-3
Secondary Outcomes
- 12-lead ECG(Screening, Day 1)
- Safety Labs (Hematology)(Screening, Days -1, 2, 3)
- Adverse Events reporting(throughout study)
- Safety Labs (Urinalysis)(Screening, Days -1, 2, 3)
- Actual values, rate of rise, rate of decline and maximum change from baseline in VEGF(Days 1, 2)
- Actual values, rate of rise, rate of decline and maximum change from baseline in Hepcidin(Days 1, 2)
- Safety Labs (Chemistry)(Screening, Day -1, 2, 3)
- Vital Signs (blood pressure and heart rate)(Screening, Days 1, 2, 3)
- Clinical Monitoring/Observation(throughout)
- Actual values, rate of rise, rate of decline and maximum change from baseline in erythropoietin(Days 1, 2, 3)
- Actual values, rate of rise, rate of decline and maximum change from baseline in TIBC (total iron binding capacity)(Screening, Days 1, 3)