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

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Anaemia

Treatments: Drug: GSK1278863; Drug: GSK1278863 matching Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02689206

2015-004790-32 (EudraCT Number)

204836

Details and patient eligibility

About

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.

Enrollment: 103 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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103 participants in 5 patient groups, including a placebo group

GSK1278863 10 mg

Experimental group

Description:

Subject will receive 10 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days).

Treatment:

Drug: GSK1278863

GSK1278863 15 mg

Experimental group

Description:

Subject will receive 15 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days).

Treatment:

Drug: GSK1278863

GSK1278863 25 mg

Experimental group

Description:

Subject will receive 25 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days).

Treatment:

Drug: GSK1278863

GSK1278863 30 mg

Experimental group

Description:

Subject will receive 30 mg of GSK1278863 three-times weekly for 4 weeks (up to 29 days).

Treatment:

Drug: GSK1278863

Placebo

Placebo Comparator group

Description:

Subject will receive GSK1278863 matching placebo three-times weekly for 4 weeks (up to 29 days).

Treatment:

Drug: GSK1278863 matching Placebo