Assessment of the Pharmacokinetics of GSK1278863 and Metabolites in Normal Subjects and Subjects With Renal Impairment

NCT01406340 | Terminated Phase 1

• 1 other identifier: 115573
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 3

Brief Summary

This will be an open-label, parallel-group study to evaluate the pharmacokinetics of GSK1278863 and metabolites in normal subjects and subjects with impaired renal function, including those who are hemodialysis dependent. GSK1278863 will be administered once daily for 14 days to normal subjects and subjects with Stage 3 and Stage 4 renal function, and 15 days to subjects with Stage 5 renal function. Pharmacokinetic assessments will be made on Days 1 and 14 (normal subjects, subjects with Stage 3 and Stage 4 renal function) or Days 14 and 15 (dialysis and non-dialysis days; Stage 5).

Conditions

Anaemia

Outcome Measures

Primary Outcomes (3)

• Area under the concentration-time curve over the dosing interval . Composite of Pharmacokinetics

  Area under the concentration-time curve over the dosing interval of GSK1278863 and metabolites on Day 1 and Day 14 for normal subjects and subjects with Stage 3/4 renal function; Area under the concentration-time curve over the dosing interval of GSK1278863 and metabolites on Day 14 (dialysis) and Day 15 (non-dialysis) for subjects with Stage 5 renal function.

  Blood samples will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72hr post dosing on Day 1 and Day 14 for normal and Stage3/4 subjects, and on Day 14 and Day 15 for Stage 5 subjects

• Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. Composite of Pharmacokinetics

  Area under the concentration-time curve from time zero (pre-dose) of GSK1278863 and metabolites on Day 1 for normal subjects and subjects with Stage 3/4 renal functione-dose) extrapolated to infinite time for

  Blood samples will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72hr post dosing on Day 1 in normal and Stage3/4 subjects

• Maximum observed concentration. Composite of Pharmacokinetics

  Maximum observed concentration of GSK1278863 and metabolites on Day 1 and Day 14 for normal subjects and subjects with Stage 3/4 renal function; Maximum observed concentration of GSK1278863 and metabolites on Day 14 and Day 15 for subjects with Stage 5 renal function.

  Blood samples will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72hr post dosing on Day 1 and Day 14 for normal and Stage3/4 subjects, and on Day 14 and Day 15 for Stage 5 subjects

Secondary Outcomes (8)

• Safety and tolerability as assessed by the number of adverse events during the dosing period.

  For normal subjects and subjects with Stage 3/4 renal function, from Day 1 to the follow-up visit at approximately Day 27. For subjects with Stage 5 renal function, from Day 1 to the follow-up visit at approximately Day 28.

• Time of occurrence of maximum observed concentration

  Day 1 and Day 14

• Terminal phase half-life

  Day 1 and Day 14

• renal clearance

  Day 14

• dialysis clearance

  Day 14

Study Arms (2)

Normal subjects and subjects with Stage 3/4 renal function

EXPERIMENTAL

Subjects will receive 5mg GSK1278863 for 14 days.

Drug: 5 mg GSK1278863

Subjects with Stage 5 renal function

EXPERIMENTAL

Subjects will receive 5mg GSK1278863 for 15 days.

Drug: 5 mg GSK1278863

Interventions

5 mg GSK1278863 DRUG

5 mg per day administered orally for 14 days for normal subjects and subjects with Stage 3/4 renal function; 5 mg per day administered orally for 15 days for subjects with Stage 5 renal function

Normal subjects and subjects with Stage 3/4 renal function; Subjects with Stage 5 renal function

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Study Participants
• Adults between 18 and 75 years of age at the time of Screening.
• A female subject is eligible to participate if she is of childbearing potential, and must agree 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. OR Non-childbearing potential as defined in the protocol.
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods in the protocol. This criterion must be followed from the time of the first dose of investigational product until completion of the Follow-up visit.
• Satisfactory medical evaluation based upon medical history, medication history, physical examination, and clinical laboratory data obtained at the screening visit.
• Body weight ≥ 45 kg and ≤ 140 kg at screening. For Stage 5 subjects, body weight is dry weight after hemodialysis.
• QTcF \< 450 msec; OR QTcF \< 480 msec in subjects with Bundle Branch Block. These should be based on average of triplicate values obtained over brief recording period at screening and Predose on Day 1.
• Vitamin B12 and folate above the lower limit of normal 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.
• Has normal creatinine clearance (CLCR) via the Cockcroft-Gault equation, using serum creatinine and demographic data, obtained at Screening. Normal subjects should have no greater than trace blood or protein on Screening urinalysis.
• A hemoglobin value at screening is greater than the lower limit of the reference range for the local laboratory and less than or equal to 16.0g/dL
• No greater than trace blood on screening urinalysis

You may not qualify if:

• Has Stage 3 or Stage 4 renal function (not receiving dialysis) as determined by estimated Glomerular Filtration Rate (eGFR) calculated by the abbreviated MDRD equation OR has Stage 5 renal function (end-stage renal failure) and has been on stable hemodialysis treatment scheduled three times weekly for 3 months prior to screening and the serum creatinine value at the Day -1 visit must be within +/- 20% of the screening value.
• Is otherwise 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 ECG.
• has clinical laboratory test results that are considered clinically stable in the opinion of the Investigator, especially if the clinical abnormality or laboratory parameter is deemed associated with the subject's underlying renal impairment.
• has AST, ALT, alkaline phosphatase and bilirubin \< or = 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Meets the following erythropoiesis stimulating agent (ESA) criteria: The subject is ESA naïve OR the subject has a scheduled ESA interval which is ≤ 7 days, ESA treatment must be discontinued for at least 7 days OR the subject has a scheduled ESA interval which is \> 7 days, ESA treatment must be discontinued for at least that scheduled interval length (e.g. discontinued ≥ 14 days for a scheduled 14 day ESA interval) AND the subject will not resume ESA treatment until completion of the Follow-up Visit.
• All Study Participants
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result at Screening.
• A positive test for HIV antibody.
• Uncontrolled hypertension (diastolic BP \>100 mmHg or systolic BP \>160 mmHg at Screening.
• A positive drugs of abuse and alcohol screen.
• History of regular alcohol consumption within 6 months of the study as described in the protocol.
• History of regular use of tobacco- or nicotine-containing products within 6 months of the study in excess of 20 cigarettes per day or equivalent.
• History of drug abuse or dependence within 6 months of the study.
• History of sensitivity to any of the investigational products, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

Miami, Florida, 33169, United States

Location

GSK Investigational Site

Orlando, Florida, 32809, 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

Related Links

• Results for study 115573 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Anemia

Interventions

GSK1278863

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

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: July 26, 2011
• First Posted: August 1, 2011
• Study Start: August 30, 2011
• Primary Completion: August 31, 2013
• Study Completion: August 31, 2013
• Last Updated: June 28, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (3)