Clinical trial NCT01587898: 4 Week Correction Study in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Undergoing Dialysis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anaemia
Keywords: Anemia
Prolyl hydroxylase inhibitor
Hemoglobin
Chronic kidney disease
pharmacokinetics
recombinant human erythropoietin
GSK1278863
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2012-04-30
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Age and weight: \>/= 18 years of age and \>/= 45 kg.
2. 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.
3. 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..
4. KDOQI CKD stages 3/4/5 defined by eGFR using the Modification of Diet for Renal Disease (MDRD).
5. Hgb: Hgb concentrations 8.5-11.0 g/dL (inclusive) as outlined in Section 4.2.
6. Vitamin B12: Above the lower limit of the reference range (may rescreen in 2 months).
7. Folate: \>/=2.0 ng/mL at Screening. May rescreen in a month.
8. Ferritin: \>/=40 ng/mL with the absence of microcytic or hypochromic RBCs.
9. TSAT within the reference range.
10. 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).
11. QTc: QTcB \<470 msec or QTcB \<480 msec in subjects with bundle branch block obtained at Screening Visit, based on Central Reader's interpretation.
12. Females: Eligible to participate if she is of childbearing potential, and must agree to use approved contraception methods from Screening until completion of the Follow-up Visit OR of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation of hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)\>40 MIU/ml and estradiol \<40 pg/ml is confirmatory\]. 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 enrollment. For most types 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.
13. Males: Must agree to use approved contraceptive methods from the time of Screening until completion of the Follow-up Visit.

Exclusion Criteria:

1. Dialysis: Planning to initiate dialysis during the study or who have a high potential for initiating dialysis during study participation.
2. Renal transplant: Renal transplant anticipated or scheduled within the study time period or subjects with a functioning renal transplant.
3. Total CPK: \>5x the upper limit of the reference range.
4. HIV: Positive HIV antibody.
5. History of myocardial infarction or acute coronary syndrome within the prior 6 months.
6. History of stroke or TIAs.
7. Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
8. Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or lack of treatment, defined as DBP \>100 mmHg or SBP\>160 mmHg.
9. 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.
10. 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).
11. Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).
12. Hematological disease: Any hematological disease including those affecting platelets, the coagulation disorders (e.g., Protein C or S deficiency) or red blood cells (e.g. sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia) or any other cause of anemia other than renal disease.
13. 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 \[alkaline phosphatase, ALT or AST \> 2.0 x upper limit of normal (ULN) or total bilirubin \> 1.5 x ULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
14. Major surgery: Within the prior 12 weeks or planned during the study.
15. Transfusion: Blood transfusion within the prior 12 weeks or an anticipated need for blood transfusion during the study.
16. Ulcer and Active GI Bleeding: Evidence of active peptic, duodenal, or esophageal ulcer disease or active GI bleeding within the prior 12 weeks.
17. Acute infection: Clinical evidence of acute infection or history of infection requiring intravenous (IV) antibiotic therapy the eight weeks prior to Screening through Day 1 (randomization).
18. Malignancy: History of malignancy within 5 years of Screening or are receiving treatment for cancer or those with 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.
19. Hyperparathyroidism: Clinically significant hyperparathyroidism in the opinion of the Investigator, including subjects with parathyroid hormone (PTH) values ≥600 pg/mL.
20. Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months, or macular edema requiring treatment.
21. Severe reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
22. Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Screening until the Follow-up Visit.
23. Androgens: New androgen therapy or changes to pre-existing androgen regimen within prior 12 weeks.
24. Prior investigational product exposure: The subject has participated in a clinical trial and has received an experimental investigational product within prior 30 days.
25. Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
26. Other conditions: Any condition which in the investigators opinion should exclude the subject from participating in the study.
27. Pregnancy and lactation: Pregnant females as determined by positive urine hCG test, OR women who are lactating at Screening or during the trial.

Primary outcomes:
measure: Modeled Hgb Change From Baseline Over 4 Weeks of Treatment
timeFrame: Baseline (average of Week -2, -1 and Day 1) and Week 4
Secondary outcomes:
measure: Model-Adjusted Maximum Hgb Changes Over 4 Weeks
timeFrame: Baseline (average of Week -2 , -1 and Day 1 visits) and 4 weeks
measure: Number of Participants Achieving an Increase of 0.5, 1.0, 1.5 and 2.0 g/dL in Hgb
timeFrame: Up to 4 weeks
measure: Percentage of Participants Achieving an Increase of 0.5, 1.0, 1.5 and 2.0 g/dL in Hgb
timeFrame: Up to 4 weeks
measure: Number of Participants Who Reached Hgb Stopping Criteria
timeFrame: Up to Week 4
measure: Change From Baseline in Hepcidin at Week 2 and Week 4
timeFrame: Baseline (Pre-dose on Day 1), Week 2 and 4
measure: Change From Baseline in Ferritin at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in Transferrin at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in Transferrin Saturation at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in Total Iron Binding Capacity at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in Total Iron at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in High Sensitivity C-reactive Protein (hsCRP) at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in Hematocrit and Reticulocytes Over 4 Weeks
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, and 4
measure: Change From Baseline in Erythropoietin at Week 2 and Week 4
timeFrame: Baseline (Day 1 Pre-dose), Week 2 and 4
measure: Change From Baseline in Red Blood Cells Count Over 4 Weeks
timeFrame: Baseline (Day 1 pre-dose), week 1, 2, 3, 4
measure: Change From Baseline in Vascular Endothelial Growth Factor (VEGF) at Week 2 and Week 4
timeFrame: Baseline (Pre-dose), week 2 and 4
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 6 weeks
measure: Number of Participants Discontinuing the Study Treatment Due to AEs
timeFrame: Up to 6 weeks
measure: 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
timeFrame: Baseline (Day 1 pre-dose), Week 2, 4, and 6
measure: Absolute Values of Albumin, Apolipoprotein A1, Apolipoprotein Total, Total Protein at Baseline (Day 1), Week 2, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 2, 4, and 6
measure: Absolute Values of Calcium, Chloride, Cholesterol, Glucose, Inorganic Phosphorus, Potassium, Sodium at Baseline (Day 1), Week 2, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 2, 4, and 6
measure: Absolute Values of Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin at Baseline (Day 1), Week 2, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 2, 4, and 6
measure: Absolute Values of Urine Total Protein/Creatinine Ratio at Baseline (Day 1), Week 2, 4, and 6
timeFrame: Baseline (Day 1), Week 2, 4, and 6
measure: Change From Baseline Values of ALT, ALP, AST, CK at Week 2, 4, and 6
timeFrame: Baseline (Day 1), Week 2, 4, and 6
measure: Change From Baseline Values of Albumin, Apolipoprotein A1, Apolipoprotein Total, Total Protein at Week 2, 4, and 6
timeFrame: Baseline (Day 1), Week 2, 4, and 6
measure: Change From Baseline Values of Calcium, Chloride, Cholesterol, Glucose, Inorganic Phosphorus, Potassium, Sodium at Week 2, 4, and 6
timeFrame: Baseline (Day 1), Week 2, 4, and 6
measure: Change From Baseline Values of Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin at Week 2, 4, and 6
timeFrame: Baseline (Day 1), Week 2, 4, and 6
measure: Change From Baseline Values of Urine Total Protein/Creatinine Ratio at Week 2, 4, and 6
timeFrame: Baseline (Day 1), Week 2, 4, and 6
measure: Absolute Values of Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, WBC Count (Absolute) at Baseline, Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Absolute Values of Mean Corpuscle Volume at Baseline, Week 1, 2, 3, 4 and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Absolute Values of Mean Corpuscle Hgb Concentration at Baseline (Day 1), Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Absolute Values of Reticulocyte Count at Baseline (Day 1), Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelet Count, WBC Count (Absolute) at Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1), Week 1, 2, 3, 4, and 6
measure: Change From Baseline in Mean Corpuscle Volume at Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1), Week 1, 2, 3, 4, and 6
measure: Change From Baseline in Mean Corpuscle Hgb Concentration at Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1), Week 1, 2, 3, 4, and 6
measure: Absolute Values of Systolic Blood Pressure and Diastolic Blood Pressure Baseline, Week 1, Week 2, Week 3, Week 4 and Week 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Absolute Values of Heart Rate at Baseline (Day 1), Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Change From Baseline in Heart Rate at Week 1, 2, 3, 4, and 6
timeFrame: Baseline (Day 1 pre-dose), Week 1, 2, 3, 4, and 6
measure: Absolute Electrocardiogram (ECG) Parameter Values at Baseline (Screening), Week 2, 4, and 6
timeFrame: Baseline (Screening), Week 2, 4, and 6
measure: Change From Baseline in ECG Parameters at Week 2, 4 and 6
timeFrame: Baseline (Screening), Week 2, 4, and 6
measure: Mean Maximum Plasma Concentration (Cmax) of GSK1278863 and GSK1278863 Metabolites
timeFrame: 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).
measure: Mean Steady State Area Under the Curve (AUC) of GSK1278863 and GSK1278863 Metabolites
timeFrame: 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)
Other outcomes:
Locations:
city: Azusa
country: United States
facility: GSK Investigational Site
state: California
city: Bakersfield
country: United States
facility: GSK Investigational Site
state: California
city: Chino
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: North Hollywood
country: United States
facility: GSK Investigational Site
state: California
city: Orange
country: United States
facility: GSK Investigational Site
state: California
city: Riverside
country: United States
facility: GSK Investigational Site
state: California
city: San Dimas
country: United States
facility: GSK Investigational Site
state: California
city: West Hills
country: United States
facility: GSK Investigational Site
state: California
city: Yuba City
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Daytona Beach
country: United States
facility: GSK Investigational Site
state: Florida
city: Edgewater
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Ocala
country: United States
facility: GSK Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Port Charlotte
country: United States
facility: GSK Investigational Site
state: Florida
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Evanston
country: United States
facility: GSK Investigational Site
state: Illinois
city: Gurnee
country: United States
facility: GSK Investigational Site
state: Illinois
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Asheville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Wilmington
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Winston-Salem
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Bethlehem
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Erie
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Uniontown
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Arlington
country: United States
facility: GSK Investigational Site
state: Texas
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Corsicana
country: United States
facility: GSK Investigational Site
state: Texas
city: Greenville
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Temple
country: United States
facility: GSK Investigational Site
state: Texas
city: Silverdale
country: United States
facility: GSK Investigational Site
state: Washington
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Brampton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sudbury
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Aschaffenburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Demmin
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Lehrte
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hamburg
country: Germany
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.
citation: Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, Lepore JJ, Cobitz AR. Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia. J Am Soc Nephrol. 2016 Apr;27(4):1234-44. doi: 10.1681/ASN.2014111139. Epub 2015 Oct 22.