A Four-week Phase IIa, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center Study to Evaluate the Safety, Efficacy and Pharmacokinetics of GSK1278863 in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Taking Recombinant Human Erythropoietin and Are Not Undergoing Dialysis
Overview
- Phase
- Phase 2
- Intervention
- GSK1278863
- Conditions
- Anaemia
- Sponsor
- GlaxoSmithKline
- Enrollment
- 72
- Locations
- 1
- Primary Endpoint
- Modeled Hgb Change From Baseline Over 4 Weeks of Treatment
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This is a four-week Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to evaluate the safety, efficacy and pharmacokinetics of GSK1278863 in approximately 68 subjects with anemia associated with chronic kidney disease who are not taking rhEPO and are not undergoing dialysis. The range of Hgb values for study eligibility is 8.5-11.0 g/dL. Eligible subjects will be randomized in equal proportions to receive once daily (QD) placebo or GSK1278863 0.5 mg, 2 mg or 5 mg in a double-blind fashion.
Detailed Description
This is a four-week Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to evaluate the safety, efficacy and pharmacokinetics of GSK1278863 in approximately 68 subjects with anemia associated with chronic kidney disease who are not taking rhEPO and are not undergoing dialysis. The study consists of a screening phase of up to 2 weeks, a 4-week treatment phase and a 2-week follow-up phase. The range of Hgb values for study eligibility is 8.5-11.0 g/dL. Eligible subjects will be randomized in equal proportions to receive once daily (QD) placebo or GSK1278863 0.5 mg, 2 mg or 5 mg in a double-blind fashion. Study treatment will be stopped if Hgb values fall outside of the range pre-specified in the protocol. This study aims to estimate the relationship between dose of GSK1278863 and Hgb response for correcting anemia in non-dialysis subjects with CKD who are not taking rhEPO (NDD). In addition, the study will characterize the effect of GSK1278863 on various pharmacokinetic/pharmacodynamic (PK/PD) markers, and will investigate the safety and tolerability of GSK1278863. An early interim analysis of the Hgb data is planned after approximately 20 subjects from cohort 1 have completed 3 weeks of treatment. Depending upon the interim findings, a second cohort of subjects may be added to investigate an additional GSK1278863 dose arm. Recruitment to the first cohort will continue during the interim analysis. A second interim analysis is planned after approximately 48 subjects from cohort 1 have completed 4 weeks treatment. The purpose of this interim is three-fold, to investigate whether a second cohort of subjects may be added, to facilitate early development of dose-response and PK/PD statistical models, and to generate interim results to facilitate design and dosing decisions for the next trial. Subject completion is defined as completion of all study phases including the follow-up phase.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age and weight: \>/= 18 years of age and \>/= 45 kg.
- •Not routinely undergoing dialysis, regardless of the modality (either hemodialysis or peritoneal dialysis) or dialysis planned during the time the subject would be enrolled in the study.
- •No current or prior rhEPO use within the past 7 weeks; e.g., epoetins (or their biosimilars), darbepoetin, Mircera (methoxy polyethylene glycol epoetin beta), peginesatide or their biosimilars..
- •KDOQI CKD stages 3/4/5 defined by eGFR using the Modification of Diet for Renal Disease (MDRD).
- •Hgb: Hgb concentrations 8.5-11.0 g/dL (inclusive) as outlined in Section 4.
- •Vitamin B12: Above the lower limit of the reference range (may rescreen in 2 months).
- •Folate: \>/=2.0 ng/mL at Screening. May rescreen in a month.
- •Ferritin: \>/=40 ng/mL with the absence of microcytic or hypochromic RBCs.
- •TSAT within the reference range.
- •Iron replacement therapy: Stable maintenance dose of oral iron replacement therapy, if required, that will be maintained throughout the study. NOTE: IV iron replacement therapy is not allowed the two weeks prior to Screening through the end of the study (Week 6).
Exclusion Criteria
- •Dialysis: Planning to initiate dialysis during the study or who have a high potential for initiating dialysis during study participation.
- •Renal transplant: Renal transplant anticipated or scheduled within the study time period or subjects with a functioning renal transplant.
- •Total CPK: \>5x the upper limit of the reference range.
- •HIV: Positive HIV antibody.
- •History of myocardial infarction or acute coronary syndrome within the prior 6 months.
- •History of stroke or TIAs.
- •Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
- •Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or lack of treatment, defined as DBP \>100 mmHg or SBP\>160 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), or other thrombosis related condition) within the prior 6 months.
- •Pulmonary hypertension: Known pulmonary hypertension and those at higher risk (than normally associated with CKD) for pre-existing elevation in pulmonary pressure (e.g., significant heart failure or lung disease requiring supplemental oxygen, or those with connective tissue diseases).
Arms & Interventions
0.5mg GSK1278863
Once daily
Intervention: GSK1278863
2mg GSK1278863
Once daily
Intervention: GSK1278863
5mg GSK1278863
Once daily
Intervention: GSK1278863
Placebo
Once daily
Intervention: Placebo
Outcomes
Primary Outcomes
Modeled Hgb Change From Baseline Over 4 Weeks of Treatment
Time Frame: Baseline (average of Week -2, -1 and Day 1) and Week 4
Modeled Hgb change from baseline over 4 weeks was derived using a random coefficient mixed effects linear regression model. The model included fixed effects for baseline Hgb, treatment and a treatment by day interaction. Random effects was fitted in the intercept and the slope over time. All data up until investigational product discontinuation was included for Hgb efficacy evaluable participants; where efficacy evaluable was defined as having a baseline and at least 2 on-treatment Hgb assessments. Baseline was the average of Week -2 , Week -1 and Day 1 visits. The change from Baseline was calculated by subtracting the Baseline value from the individual post-dose visit values.
Secondary Outcomes
- Model-Adjusted Maximum Hgb Changes Over 4 Weeks(Baseline (average of Week -2 , -1 and Day 1 visits) and 4 weeks)
- Number of Participants Achieving an Increase of 0.5, 1.0, 1.5 and 2.0 g/dL in Hgb(Up to 4 weeks)
- Percentage of Participants Achieving an Increase of 0.5, 1.0, 1.5 and 2.0 g/dL in Hgb(Up to 4 weeks)
- Number of Participants Who Reached Hgb Stopping Criteria(Up to Week 4)
- Change From Baseline in Hepcidin at Week 2 and Week 4(Baseline (Pre-dose on Day 1), Week 2 and 4)
- Change From Baseline in Ferritin at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in Transferrin at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in Transferrin Saturation at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in Total Iron Binding Capacity at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in Total Iron at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in High Sensitivity C-reactive Protein (hsCRP) at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in Hematocrit and Reticulocytes Over 4 Weeks(Baseline (Day 1 pre-dose), Week 1, 2, 3, and 4)
- Change From Baseline in Erythropoietin at Week 2 and Week 4(Baseline (Day 1 Pre-dose), Week 2 and 4)
- Change From Baseline in Red Blood Cells Count Over 4 Weeks(Baseline (Day 1 pre-dose), week 1, 2, 3, 4)
- Change From Baseline in Vascular Endothelial Growth Factor (VEGF) at Week 2 and Week 4(Baseline (Pre-dose), week 2 and 4)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to 6 weeks)
- Number of Participants Discontinuing the Study Treatment Due to AEs(Up to 6 weeks)
- Absolute Values of Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase (CK) at Baseline (Day 1), Week 2, 4, and 6(Baseline (Day 1 pre-dose), Week 2, 4, and 6)
- Absolute Values of Albumin, Apolipoprotein A1, Apolipoprotein Total, Total Protein at Baseline (Day 1), Week 2, 4, and 6(Baseline (Day 1 pre-dose), Week 2, 4, and 6)
- Absolute Values of Calcium, Chloride, Cholesterol, Glucose, Inorganic Phosphorus, Potassium, Sodium at Baseline (Day 1), Week 2, 4, and 6(Baseline (Day 1 pre-dose), Week 2, 4, and 6)
- Change From Baseline Values of Albumin, Apolipoprotein A1, Apolipoprotein Total, Total Protein at Week 2, 4, and 6(Baseline (Day 1), Week 2, 4, and 6)
- Change From Baseline Values of Calcium, Chloride, Cholesterol, Glucose, Inorganic Phosphorus, Potassium, Sodium at Week 2, 4, and 6(Baseline (Day 1), Week 2, 4, and 6)
- Change From Baseline Values of Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin at Week 2, 4, and 6(Baseline (Day 1), Week 2, 4, and 6)
- Absolute Values of Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin at Baseline (Day 1), Week 2, 4, and 6(Baseline (Day 1 pre-dose), Week 2, 4, and 6)
- Absolute Values of Urine Total Protein/Creatinine Ratio at Baseline (Day 1), Week 2, 4, and 6(Baseline (Day 1), Week 2, 4, and 6)
- Change From Baseline Values of ALT, ALP, AST, CK at Week 2, 4, and 6(Baseline (Day 1), Week 2, 4, and 6)
- Change From Baseline Values of Urine Total Protein/Creatinine Ratio at Week 2, 4, and 6(Baseline (Day 1), Week 2, 4, and 6)
- Absolute Values of Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, WBC Count (Absolute) at Baseline, Week 1, 2, 3, 4, and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Absolute Values of Mean Corpuscle Volume at Baseline, Week 1, 2, 3, 4 and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Absolute Values of Mean Corpuscle Hgb Concentration at Baseline (Day 1), Week 1, 2, 3, 4, and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Absolute Values of Reticulocyte Count at Baseline (Day 1), Week 1, 2, 3, 4, and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count, WBC Count (Absolute) at Week 1, 2, 3, 4, and 6(Baseline (Day 1), Week 1, 2, 3, 4, and 6)
- Change From Baseline in Mean Corpuscle Volume at Week 1, 2, 3, 4, and 6(Baseline (Day 1), Week 1, 2, 3, 4, and 6)
- Change From Baseline in Mean Corpuscle Hgb Concentration at Week 1, 2, 3, 4, and 6(Baseline (Day 1), Week 1, 2, 3, 4, and 6)
- Absolute Values of Systolic Blood Pressure and Diastolic Blood Pressure Baseline, Week 1, Week 2, Week 3, Week 4 and Week 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 1, 2, 3, 4, and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Absolute Values of Heart Rate at Baseline (Day 1), Week 1, 2, 3, 4, and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Change From Baseline in Heart Rate at Week 1, 2, 3, 4, and 6(Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6)
- Absolute Electrocardiogram (ECG) Parameter Values at Baseline (Screening), Week 2, 4, and 6(Baseline (Screening), Week 2, 4, and 6)
- Change From Baseline in ECG Parameters at Week 2, 4 and 6(Baseline (Screening), Week 2, 4, and 6)
- Mean Maximum Plasma Concentration (Cmax) of GSK1278863 and GSK1278863 Metabolites(Day 1 (pre-dose), Week 2 (first samples was collected approximately between 4 to 8 h and then 1, 2 and 3 h after this first sample) and Week 4 (Pre-dose 1, 2 and 3 h post-dose).)
- Mean Steady State Area Under the Curve (AUC) of GSK1278863 and GSK1278863 Metabolites(Day 1 (pre-dose), Week 2 (first samples was collected approximately between 4 to 8 h and then 1, 2 and 3 h after this first sample) and Week 4 (Pre-dose 1, 2 and 3 h post-dose))