Clinical trial NCT02689206: Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of GSK1278863 in Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease Who Are Switched From a Stable Dose of an Erythropoiesis-stimulating Agent
Official title: A 29-day, Randomized, Double-blinded, Placebo-controlled, Parallel-group, Multi-center Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of GSK1278863 in Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease Who Are Switched From a Stable Dose of an Erythropoiesis-stimulating Agent
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anaemia
Keywords: Chronic kidney disease
Efficacy
Erythropoiesis-stimulating agent
GSK1278863
Safety
Hemodialysis-dependent anemia
Pharmacokinetics
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-02-23
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: GSK1278863 is an orally available, hypoxia-inducible factor - prolyl hydroxylase inhibitor, currently being investigated as a treatment for anemia associated with chronic kidney disease. GSK1278863 has been given as a once daily regimen in clinical studies to date. However, physicians in countries that use a three-times weekly hemodialysis schedule prefer to give the anemia medicine at the same time as the dialysis session. This study will test how well GSK1278863 can maintain hemoglobin levels when given three-times weekly, for 29 days.

This study will describe the relationship between hemoglobin and GSK1278863 given three-times weekly. The data from this study will allow for conversion of once daily doses to three-times weekly doses.


Eligibility criteria: Inclusion Criteria:

* More than or equal to 18 years of age, at the time of signing the informed consent.
* Hemoglobin: Stable Hemoglobin 9.0 - 11.5 gram per deciliter (g/dL).
* Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three to five times weekly for at least 4 weeks prior to Day -28 Screening through Day 29.
* Dialysis adequacy: A single pool Kt/Vurea of \>=1.2 based on a historical value obtained within the prior three months 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 percent. NOTE: Only needs confirming at Day -28.
* Erythropoiesis-stimulating agent (ESA)dose: Treated with the same ESA (epoetins or their biosimilars, or darbepoetin or methoxy polyethylene glycol \[PEG\]-epoetin beta) with total weekly dose varying by no more than 50 percent during the 4 weeks prior to Day -28.
* Iron replacement therapy: Subjects may be on stable maintenance oral or intravenous (IV) (\<=100 milligram (mg)/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to Day -28, during the screening phase, and through the 29 days of treatment.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in study protocol.

Exclusion Criteria:

* Dialysis modality: Planned change from HD to peritoneal dialysis within the study time period.
* Renal transplant: Planned for living-related kidney transplant.
* High ESA dose: An epoetin dose of \>=360 international unit (IU)/kilogram (kg)/week IV or \>=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of \>=1.8 microgram (mcg)/kg/week IV or SC or methoxy PEG-epoetin beta dose of \>= 2.2 mcg/kg/week within the prior 8 weeks through Day 1 (randomization).
* Administration of methoxy PEG-epoetin beta within the prior 4 weeks through Day 1 (randomization).
* Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening through Day 1 (randomization).
* Stroke or transient ischemic attack: Within 8 weeks prior to Screening though Day 1 (randomization).
* Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Screening through Day 1 (randomization).
* Correction of Q-T Interval using Bazett's formula (QTcB): QTcB \>500 millisecond (msec) or QTcB \>530 msec in subjects with Bundle Branch Block. There is no correction of Q-T Interval (QTc) exclusion for subjects with a predominantly paced rhythm.
* Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Screening through Day 1 (randomization).
* 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 of chronic disease other than renal disease diagnosed prior to Screening though Day 1 (randomization).
* 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 \[alanine transaminase (ALT) or aspartate transaminase (AST) \>2x upper limit of normal (ULN) or total bilirubin \>1.5xULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participating in the study.

NOTE: Those with Hepatitis B or Hepatitis C are eligible provided these exclusions are not met.

* Major surgery: Major surgery (excluding vascular access surgery) within the 8 weeks prior to Screening, during the Screening phase, or planned during the study.
* Transfusion: Blood transfusion within the 8 weeks prior to Screening, during the Screening phase 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 through Day 1 (randomization).
* Acute Infection: Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 4 weeks prior to Screening through Day 1 (randomization). NOTE: IV antibiotics as prophylaxis are allowed.
* Malignancy: History of malignancy within the two years prior to randomization or currently receiving treatment for cancer, or has a known \>=4 centimeter complex kidney cyst (i.e. Bosniak Category II F, III of IV). NOTE: ONLY exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=8 weeks prior to Screening.
* 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 (as per protocol) from Screening 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 through Day 1 (randomization).
* Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
* Females ONLY: A female subject is not eligible to participate if she is pregnant \[as confirmed by a positive serum human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only\], breastfeeding, and if of reproductive potential does not agree to follow one of the options listed in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP.
* Vitamin B12: At or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
* Folate: \<2.0 nanogram (ng) per millilitre (mL) (4.5 nanomole/liter \[L\]) (may rescreen in a minimum of 4 weeks).
* Ferritin: \<100 ng/mL (\<100 mcg/L).
* Transferrin saturation (TSAT): \<20 percent.

Primary outcomes:
measure: Change From Baseline in Hgb Levels at Day 29
timeFrame: Baseline and Day 29
Secondary outcomes:
measure: Maximum Observed Change From Baseline in Plasma Erythropoietin (EPO)
timeFrame: Baseline and up to Day 29
measure: Maximum Observed Percent Change From Baseline in Vascular Endothelial Growth Factor (VEGF)
timeFrame: Baseline and up to Day 29
measure: Percent Change From Baseline in Hepcidin at Day 29
timeFrame: Baseline and Day 29
measure: Change From Baseline in Hematocrit Levels
timeFrame: Baseline and Day 29
measure: Change From Baseline in Red Blood Cell (RBC) Count
timeFrame: Baseline and Day 29
measure: Change From Baseline in Reticulocyte Count
timeFrame: Baseline and Day 29
measure: Change From Baseline in Reticulocyte Hemoglobin (CHr)
timeFrame: Baseline and Day 29
measure: Area Under the Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) and AUC From Time Zero to Infinity (AUC[0-inf]) of Dapro
timeFrame: Pre-dose on Day 1; 6-10 hours, 7-11 hours, 8-12 hours, 9-13 hours post dose on Day 15; pre-dose and 1, 2, 3 hours post-dose on Day 29
measure: Maximum Observed Concentration of Dapro in Plasma (Cmax)
timeFrame: Pre-dose on Day 1; 6-10 hours, 7-11 hours, 8-12 hours, 9-13 hours post dose on Day 15; pre-dose and 1, 2, 3 hours post-dose on Day 29
measure: Time to Reach Cmax (Tmax) and Apparent Terminal Half-life (t1/2) of Dapro
timeFrame: Pre-dose on Day 1; 6-10 hours, 7-11 hours, 8-12 hours, 9-13 hours post dose on Day 15; pre-dose and 1, 2, 3 hours post-dose on Day 29
measure: Number of Participants Who Discontinued Study Treatment
timeFrame: Up to Day 43
measure: Number of Participants With AEs and Serious Adverse Events (SAEs)
timeFrame: Up to Day 43
measure: Sodium, Potassium, Glucose, Calcium, Phosphate Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Albumin and Protein Levels in Blood at Indicated Tme Points
timeFrame: Up to Day 43
measure: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (Alk. Phosph) Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Bilirubin, Direct Bilirubin and Indirect Bilirubin Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Change From Baseline in Sodium, Potassium, Glucose, Calcium and Phosphate Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in Albumin and Protein Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in ALT, AST, Alk. Phosph. Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in Bilirubin, Direct Bilirubin, Indirect Bilirubin Levels
timeFrame: Baseline and up to Day 43
measure: Leukocytes, Neutrophils, Basophils, Eosinophils,Lymphocytes, Monocytes, Platelet Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Mean Corpuscular Hemoglobin (MCH) Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Mean Corpuscular Hemoglobin Concentration (MCHC) Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Mean Corpuscular Volume (MCV) Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Erythrocyte Distribution Width Levels in Blood at Indicated Time Points
timeFrame: Up to Day 43
measure: Change From Baseline in MCH Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in MCHC Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in MCV Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in Erythrocyte Distribution Width Levels
timeFrame: Baseline and up to Day 43
measure: Change From Baseline in Leukocytes, Neutrophils, Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Levels
timeFrame: Baseline and up to Day 43
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings at Indicated Time Points
timeFrame: Up to Day 29
measure: Change From Baseline in ECG Mean Heart Rate
timeFrame: Baseline and Day 29
measure: Change From Baseline in ECG Parameters Including PR Interval, QRS Duration, QT Interval and QTcB
timeFrame: Baseline and Day 29
measure: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Values at Pre-dialysis and Post-dialysis
timeFrame: Up to Day 43
measure: Pulse Rate Values at Pre-dialysis and Post-dialysis
timeFrame: Up to Day 43
measure: Weight Values at Post-dialysis
timeFrame: Up to Day 43
measure: Change From Baseline in SBP and DBP Values at Pre-dialysis and Post-dialysis
timeFrame: Up to Day 43
measure: Change From Baseline in Pulse Rate Value at Pre-dialysis and Post-dialysis
timeFrame: Up to Day 43
measure: Change From Baseline in Weight at Post-dialysis
timeFrame: Up to Day 43
Other outcomes:
Locations:
city: Northridge
country: United States
facility: GSK Investigational Site
state: California
city: San Dimas
country: United States
facility: GSK Investigational Site
state: California
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Greenbelt
country: United States
facility: GSK Investigational Site
state: Maryland
city: Roseville
country: United States
facility: GSK Investigational Site
state: Michigan
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Greenfield Park
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Stuttgart
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Villingen-Schwenningen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Darmstadt
country: Germany
facility: GSK Investigational Site
city: Krasnodar
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Mytischi
country: Russian Federation
facility: GSK Investigational Site
city: Omsk
country: Russian Federation
facility: GSK Investigational Site
city: Penza
country: Russian Federation
facility: GSK Investigational Site
city: St-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Almería
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Granollers, Barcelona
country: Spain
facility: GSK Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: GSK Investigational Site
city: Lleida
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Malaga
country: Spain
facility: GSK Investigational Site
city: Manises (Valencia)
country: Spain
facility: GSK Investigational Site
city: San Sebastian de los Reyes
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Valladolid
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Bailey CK, Caltabiano S, Cobitz AR, Huang C, Mahar KM, Patel VV. A randomized, 29-day, dose-ranging, efficacy and safety study of daprodustat, administered three times weekly in patients with anemia on hemodialysis. BMC Nephrol. 2019 Oct 16;20(1):372. doi: 10.1186/s12882-019-1547-z.
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.