Clinical trial NCT02019719: Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Japanese Hemodialysis-Dependent Subjects With Anemia Associated With Chronic Kidney Disease
Official title: A 4-Week, Phase II, Randomized, Double-Blind, Dose-Ranging, Placebo-Controlled, Parallel-Group, Multi-Center Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Japanese Hemodialysis-Dependent Subjects With Anemia Associated With Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anaemia
Keywords: Hemodialysis
GSK1278863
Pharmacokinetics
Erythropoiesis Stimulating Agents
Chronic Kidney Disease
Hemoglobin
Recombinant Erythropoietin
Prolyl Hydroxylase Inhibitor
Anemia
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-12-24
Enrollment: 97
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to characterize the relationship between dose of GSK1278863 and hemoglobin (Hgb) response in hemodialysis-dependent (HDD) subjects with anemia associated with chronic kidney disease (CKD). It is anticipated that the data generated will enable selection of the starting dose(s) and optimize dose adjustment regimen(s) for Phase 3 clinical trials. This study will consist of a screening phase of 3-9 weeks, a 4-week treatment phase and a follow-up visit approximately 4 weeks after completing treatment.


Eligibility criteria: Inclusion Criteria:

* Age (Informed concent): Japanese \>=20 years of age
* Gender (Screening 2 verification only): Female and male
* Females: must be of childbearing potential, and must agree to use one of the approved contraception methods from Screening 2 until completion of the Follow-up Visit. OR Of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone 23.0 - 116.3 million international units (MIU)/millilitre (mL) and estradiol \<= 10 picograms (pg)/mL is confirmatory\]. Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the approved contraception methods 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 enrolment. For most forms of HRT, at least 2 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. Males: must agree to use one of the approved contraceptive methods from the time of Screening 2 until completion of the Follow-up Visit.
* Corrected QT interval (QTc) (Screening 2 verification only): Bazett's Correction of QT Interval (QTcB) \<470 milliseconds (msec) or QTcB \<480 msec in subjects with bundle branch block. There is no QTc inclusion criterion for a subject with a predominantly paced rhythm.
* Dialysis frequency: On hemodialysis (HD) three times weekly for at least 8 weeks prior to Screening 2 through Day 1.
* Dialysis adequacy (Screening 2 only): A single-pool Kt/Vurea of 1.2 based on a historical value obtained within the prior month in order to ensure the adequacy of dialysis. If Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio (URR) of at least 65%.
* Hemoglobin: Target stable Hgb between 9.5-12.0 g/dL at screening.
* Stable erythropoiesis-stimulating agent (ESA) dose (Screening 2 only): Using the same ESA (epoetins or their biosimilar, or darbepoietin) with total weekly doses that varied by no more than 50% during the 4 weeks prior to Screening 2.
* Iron replacement therapy: Subjects may be on stable maintenance oral or intravenous (IV) (\<100 milligrams \[mg\]/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to Screening 2, and Screening 2 through Week 4.

Exclusion Criteria:

* Dialysis modality: Planned change from HD to peritoneal dialysis within the study time period.
* Renal transplant: Renal transplant anticipated or scheduled within the study time period.
* High ESA dose (Screening 2 verification only): As defined by an epoetin dose of \>=360 IU/kilograms (kg)/week IV or darbepoetin dose of \>=1.8 micrograms (μg)/kg/week IV within the prior 8 weeks through Screening 2.
* methoxy polyethylene glycol epoetin beta (Screening 2 verification only): Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Screening 2.
* Vitamin B12: At or below the lower limit of the reference range
* Folate: \<2.0 nanograms (ng)/mL (\<4.5 nanomoles \[nmol\]/liters \[L\])
* Iron status: Ferritine \<100 ng/mL (\<100 μg/L) AND Transferrin saturation (TSAT) \<20%
* Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening 2 through Day 1.
* Stroke or transient ischemic attack: Within the 8 weeks prior to Screening 2 through Day 1.
* Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system or symptomatic right heart failure diagnosed prior to Screening 2 through Day 1.
* Hypertension: Defined using pre-dialysis vitals of diastolic blood pressure \>100 mmHg or systolic blood pressure \>170 mmHg.
* Thrombotic disease: History of thrombotic disease (e.g., venous thrombosis such as deep vein thrombosis or pulmonary embolism, or arterial thrombosis such as new onset or worsening limb ischemia requiring intervention), except vascular access thrombosis, within the 8 weeks prior to Screening 2 through Day 1
* Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months or macular edema requiring treatment..
* Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Screening 2 through Day 1.
* Hematological disease: Any hematological disease including those affecting platelets, white or red blood cells (e.g. sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia and thalassemia), coagulation disorders (e.g., antiphospholipid syndrome, Protein C or S deficiency), or any other cause of anemia other than renal disease diagnosed prior to Screening 2 through Day 1.
* Liver disease: Current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or evidence at Screening of abnormal liver function tests \[alanine transaminase (ALT) or aspartate transaminase (AST) \>2.0 x upper limit of normal (ULN) or total bilirubin \> 1.5 x ULN\]; or other hepatic abnormalities that in the opinion of the investigator (subinvestigator) would preclude the subject from participation in the study.
* Major surgery: Major surgery (excluding vascular access surgery) within the prior 8 weeks, within the Screening 2 to Day 1 or planned during the study.
* Transfusion: Blood transfusion within the prior 8 weeks, within the Screening 2 to Day 1 or an anticipated need for blood transfusion during the study.
* Gastrointestinal (GI) bleeding: Evidence of actively bleeding peptic, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks prior to Screening 2 through Day 1.
* Acute infection: Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within 8 weeks prior to Screening 2 through Day 1.
* Malignancy: Subjects with a history of malignancy within the prior 5 years, who receiving treatment for cancer, or who have a strong family history of cancer (e.g., familial cancer disorders); with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated prior to Screening 2 through Day 1.
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product
* Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Screening 2 until the Follow-up Visit.
* Prior investigational product exposure: The Subject has participated in a clinical trial and has received an experimental investigational product within the prior 30 days from Screening 2 through Day 1.
* Pregnancy or lactation: Pregnant females as determined by positive serum Human Chorionic Gonadotrophin (hCG) test (Screening 2 only) OR women who are lactating at Screening 2 and/or Day 1 or during the trial.
* Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator would consider inappropriate to participate in the study.

Primary outcomes:
measure: Change From Baseline (CFB) in Hemaglobin (Hgb) at Week 4
timeFrame: Baseline (Day 1) and Week 4
Secondary outcomes:
measure: CFB in Hgb Upto Week 8
timeFrame: Baseline (Day 1) Upto Week 8
measure: Number of Participants Who Achieved Hgb Response at Week 4
timeFrame: Week 4
measure: Percentage of Participants Who Achieved Hgb Response at Week 4
timeFrame: Week 4
measure: Number of Participants Who Reached Pre-defined Hgb Stopping Criteria
timeFrame: Upto Week 4
measure: Maximum Observed CFB in Erythropoietin (EPO) Upto Week 4
timeFrame: Baseline (Day 1) Upto Week 4
measure: Maximum Observed Percent CFB in Peak Vascular Endothelial Growth Factor (VEGF) Upto Week 4
timeFrame: Baseline (Day 1) Upto Week 4
measure: Percent CFB in Hepcidine Upto Week 4
timeFrame: Baseline (Day 1) Upto Week 4
measure: CFB in Ferritin at Week 4
timeFrame: Baseline (Day 1) and Week 4
measure: CFB in Total Iron Binding Capacity [TIBC], Unbound Iron Binding Capacity [UIBC] and Iron at Week 4
timeFrame: Baseline (Day 1) and Week 4
measure: CFB in Transferrin at Week 4
timeFrame: Baseline (Day 1) and Week 4
measure: Percent CFB in Transferrin Saturation (TS) at Week 4
timeFrame: Baseline (Day 1) and Week 4
measure: Plasma Pharmacokinetic Concentration of GSK1278863 and Metabolites (M) at Week 4
timeFrame: Week 4
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) on Therapy
timeFrame: Upto Week 4
measure: Number of Participants With Chemistry and Hematology Data of Potential Clinical Importance (PCI) Upto Week 4
timeFrame: Upto Week 4
measure: Number of Participants With Vital Signs Parameters Systolic and Diastolic Blood Pressure (SBP,DBP) of PCI Upto Week 4
timeFrame: Upto Week 4
measure: Number of Participants With Vital Sign Parameter Heart Rate (HR) of PCI Upto Week 4
timeFrame: Upto Week 4
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings Upto Week 4
timeFrame: Upto Week 4
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Kagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Miyagi
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Niigata
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Toyama
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.