Clinical trial NCT01977573: A Study to Evaluate Safety and Efficacy of GSK1278863 in Non-Dialysis Dependent (NDD) Subjects With Anemia Associated With Chronic Kidney Diseases (CKD)
Official title: A 24-week, Phase IIB, Randomized, Controlled, Parallel Group, Multi-center Study to Evaluate the Safety and Efficacy of GSK1278863 in Subjects With Anemia Associated With Chronic Kidney Diseases Who Are Not on Dialysis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Anaemia
Keywords: Prolyl hydroxylase inhibitor
pharmacokinetics
GSK1278863
Anemia
hemoglobin
erythropoiesis stimulating agents
Chronic kidney disease
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-11-06
Enrollment: 252
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 study will be conducted in approximately 228 subjects with anemia associated with CKD who are not on dialysis. Two groups of subjects will be enrolled into the study: Group 1: recombinant human erythropoietin (rhEPO) naive subjects; Group 2: rhEPO users, who are currently receiving rhEPO. Subjects who are rhEPO naive will be randomized to receive either GSK1278863 once daily (QD) or rhEPO in a 3:1 fashion; subjects who are receiving an rhEPO before enrolling (rhEPO users) will be randomized in a 1:1 fashion to GSK1278863 QD or to the control arm. For those randomized to the control arm, the decision around whether the subject requires rhEPO, the selection of the type of rhEPO (if needed) and the choice of rhEPO dose to achieve and maintain Hgb concentrations within the target range should be based on Investigator clinical judgment, with the historical rhEPO dose and the current Hgb value being considered. The study consists of a screening phase of at least 4 weeks, a 24-week treatment phase and a follow-up visit that will occur approximately 4 weeks after completing treatment. 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.


Eligibility criteria: Inclusion Criteria:

* Age: \>=18 years of age. (Week -4 verification only)
* Gender: Female and male subjects. (Week -4 verification only) Females: If of childbearing potential, must agree to use one of the 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, hysterectomy, or oophorectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. 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.
* Corrected QT interval (QTc): Bazett's Correction of QT Interval (QTcB) \<470 milliseconds (msec) or QTcB \<480 msec in subjects with bundle branch block. There is no QTc criterion for subjects with a predominantly paced rhythm.
* CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 defined by electronic estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Hgb: Group 1 (rhEPO naïve): Baseline Hgb of 8.0-11.0 g/dL (inclusive) (USA sites only: 8.0-10.0 g/dL, inclusive); Group 2 (rhEPO users): Baseline Hgb of 9.0-11.5 g/dL (inclusive) (USA sites only: 9.0-10.5, inclusive).
* Stable rhEPO dose for rhEPO users: Group 2 subjects must be using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses that varied by no more than 50% during the 4 weeks prior to Week -4. At Day 1 (randomization), confirm that total weekly doses varied by no more than 50% during the screening period.
* Oral iron therapy: If on oral iron, then doses must not be changed for the 4 weeks prior to Week -4, during the screening phase, and through the first 4 weeks after Randomization.

Exclusion Criteria:

* Dialysis: On dialysis or planning to initiate dialysis during the study.
* Renal transplant: Pre-emptive or scheduled renal transplant.
* High rhEPO dose: An epoetin dose of \>=360 IU/kg/week intravenous (IV) or \>=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of \>=1.8 microgram per kilogram per week (mcg/kg/week) IV or SC within the prior 8 weeks through Day 1 (randomization).
* Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Day 1 (randomization).
* IV iron therapy: Use of IV iron for 4 weeks prior to Screening Week -4, during the screening phase, and through the first 4 weeks after Randomization
* Vitamin B12: Below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
* Folate: \<2.0 nanogram per millilitre (ng/mL) (\<4.5 nanomoles per liter \[nmol/L\]) (may rescreen in a minimum of 4 weeks).
* Ferritin: \<40 ng/mL (\<40 mcg/L).
* Transferrin saturation (TSAT): Below the lower limit of the reference range
* Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening through Day 1 (randomization).
* Stroke or transient ischemic attack: Within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
* Heart failure: Class III/IV heart failure as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Week -4 Screening through Day 1 (randomization), symptomatic right heart failure diagnosed prior to Week -4 Screening through Day 1 (randomization).
* Uncontrolled hypertension: Defined as diastolic blood pressure (DBP) \>100 mmHg or systolic blood pressure (SBP) \>170 mmHg at Week -4 and reconfirmed at Day 1.
* 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 Week -4 Screening through Day 1 (randomization).
* Ophthalmology disease: Meeting any ophthalmologic-related exclusion criteria determined at the Screening ophthalmology exam.
* Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Week -4 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 other than renal disease diagnosed prior to Week -4 Screening through 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 \[alanine transaminase (ALT) or aspartate transaminase (AST) \>2.0 x upper limit of normal (ULN) or total bilirubin \>1.5 x ULN\]; or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
* Major surgery: Major surgery (excluding vascular access surgery) within the prior 8 weeks, during the Week -4 Screening phase or planned during the study.
* Transfusion: Blood transfusion within the prior 8 weeks, during the Week -4 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 Week -4 Screening through Day 1 (randomization).
* Acute infection: Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
* 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 Week -4 Screening through Day 1 (randomization).
* Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (see GSK1278863 IB for list of excipients and rhEPO (refer to local product labelling for details).
* Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Week -4 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 Week -4 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.
* Patient participation: Unwillingness or inability of the subject to follow the procedures or lifestyle or dietary restrictions outlined in the protocol.
* Pregnancy or Lactation: Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test OR women who are lactating at Week -4 Screening or during the trial.

Primary outcomes:
measure: Summary of Hemoglobin (Hgb) Concentration at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: Number of Participants With Hemoglobin (Hgb) in the Target Range at Week 24
timeFrame: Week 24
measure: Number of Participants Reaching Pre-defined Hgb Stopping Criteria
timeFrame: Over a period of 24 Weeks
measure: Percent Change From Baseline in Hepcidin Concentration at Week 24
timeFrame: Baseline and Week 24
measure: Maximum Observed Change From Baseline in Serum Erythropoietin (EPO)
timeFrame: Baseline to Week 24
measure: Maximum Observed Percent Change From Baseline in Vascular Endothelial Growth Factor (VEGF)
timeFrame: Baseline and up to Week 24
measure: Percentage of Time Within, Below, and Above Hemoglobin (Hgb) Target Range, Between Weeks 12 and 24
timeFrame: Weeks 12 to 24
measure: Change From Baseline in Ferritin Concentration at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Transferrin Concentration at Week 24
timeFrame: Baseline and Week 24
measure: Percent Change From Baseline in Transferrin Saturation at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Total Iron at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Total Iron Binding Capacity (TIBC) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Reticulocyte Hemoglobin (CHr) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Hematocrit at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Red Blood Cell Count at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Reticulocyte Cell Count at Week 24
timeFrame: Baseline and Week 24
measure: Concentration of GSK1278863 and Relevant Metabolites as a Population Pharmacokinetic Endpoint
timeFrame: Day 1 (pre-dose), Week (Wk) 4 (6-12 hour, 7-13 hour, 8-14 hour, 9-15 hour post-dose), and Wk 20 (pre-dose, 1 hour, 2 hour, 3 hour post-dose)
measure: Mean Number of Dose Adjustments up to 24 Weeks
timeFrame: From Week 4 up to 24 Weeks
measure: Number of Participants With Dose Adjustments up to 24 Weeks, as a Measure of Dose Adjustment Frequency
timeFrame: From week 4 up to 24 weeks
measure: Timing of Dose Adjustments at Weeks 4, 8, 12, 16, and 20
timeFrame: From Week 4 up to Week 20
measure: Mean Total Cumulative Dose of GSK1278863 up to 24 Weeks
timeFrame: Up to 24 Weeks
measure: Mean Final Dose of GSK1278863 up to 24 Weeks
timeFrame: Up to 24 Weeks
measure: Number of Hemoglobin (Hgb) Excursions
timeFrame: Up to 24 Weeks.
measure: Number of Hemoglobin (Hgb) Cycles up to 24 Weeks
timeFrame: Up to 24 Weeks
measure: Number of Dose Cycles up to 24 Weeks
timeFrame: Up to 24 weeks
measure: Number of Participants With at Least One Hemoglobin (Hgb) Excursion up to 24 Weeks.
timeFrame: Up to 24 weeks
measure: Number of Participants With at Least One Hemoglobin (Hgb) Cycle up to 24 Weeks
timeFrame: Up to 24 weeks
measure: Number of Participants With at Least One Dose Cycle up to 24 Weeks
timeFrame: Up to 24 weeks
measure: Number of Participants Receiving Additional Therapies of Blood Transfusions, Intravenous (IV) Iron or rhEPO at Any Time Post-Baseline
timeFrame: From Day 1 up to Week 28
measure: Number of Weeks Dose Withheld Because Hemoglobin (Hgb) Exceeded the Upper Limit
timeFrame: From Week 4 up to Week 24
Other outcomes:
Locations:
city: Peoria
country: United States
facility: GSK Investigational Site
state: Arizona
city: Azusa
country: United States
facility: GSK Investigational Site
state: California
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
city: Laguna Hills
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: San Diego
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: Lauderdale Lakes
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Macon
country: United States
facility: GSK Investigational Site
state: Georgia
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Evergreen Park
country: United States
facility: GSK Investigational Site
state: Illinois
city: Shreveport
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Farmington
country: United States
facility: GSK Investigational Site
state: Missouri
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Bethlehem
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Uniontown
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Knoxville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Corsicana
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: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Liverpool
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Westmead
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Brampton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Kitchener
country: Canada
facility: GSK Investigational Site
state: Ontario
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Mississauga
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sudbury
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Pointe-Claire
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Cheb
country: Czechia
facility: GSK Investigational Site
city: Liberec
country: Czechia
facility: GSK Investigational Site
city: Louny
country: Czechia
facility: GSK Investigational Site
city: Marianske Lazne
country: Czechia
facility: GSK Investigational Site
city: Most
country: Czechia
facility: GSK Investigational Site
city: Praha 10
country: Czechia
facility: GSK Investigational Site
city: Praha 2
country: Czechia
facility: GSK Investigational Site
city: Praha 4
country: Czechia
facility: GSK Investigational Site
city: Sokolov
country: Czechia
facility: GSK Investigational Site
city: Odense C
country: Denmark
facility: GSK Investigational Site
city: Roskilde
country: Denmark
facility: GSK Investigational Site
city: Amiens cedex 1
country: France
facility: GSK Investigational Site
city: Bordeaux
country: France
facility: GSK Investigational Site
city: Caen Cedex 9
country: France
facility: GSK Investigational Site
city: Créteil Cedex
country: France
facility: GSK Investigational Site
city: Lyon Cedex 03
country: France
facility: GSK Investigational Site
city: Paris Cedex 15
country: France
facility: GSK Investigational Site
city: Sainte Foy-Lès-Lyon
country: France
facility: GSK Investigational Site
city: Mannheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Demmin
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Duesseldorf
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Székesfehérvár
country: Hungary
facility: GSK Investigational Site
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Gifu
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kyoto
country: Japan
facility: GSK Investigational Site
city: Nagano
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Shiga
country: Japan
facility: GSK Investigational Site
city: Anyang-Si Gyeonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Daegu
country: Korea, Republic of
facility: GSK Investigational Site
city: Daejeon
country: Korea, Republic of
facility: GSK Investigational Site
city: Gwangju
country: Korea, Republic of
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lublin
country: Poland
facility: GSK Investigational Site
city: Tarnow
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Zabrze
country: Poland
facility: GSK Investigational Site
city: Izhevsk
country: Russian Federation
facility: GSK Investigational Site
city: Kaluga
country: Russian Federation
facility: GSK Investigational Site
city: Khantymansiysk
country: Russian Federation
facility: GSK Investigational Site
city: Krasnodar
country: Russian Federation
facility: GSK Investigational Site
city: Krasnoyarsk
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Ulyanovsk
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Alcala de Henares
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Cordoba
country: Spain
facility: GSK Investigational Site
city: Granada
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
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: Göteborg
country: Sweden
facility: GSK Investigational Site
city: Karlstad
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
city: Uppsala
country: Sweden
facility: GSK Investigational Site
city: Örebro
country: Sweden
facility: GSK Investigational Site
city: Chelmsford
country: United Kingdom
facility: GSK Investigational Site
city: Dorchester
country: United Kingdom
facility: GSK Investigational Site
city: Dundee
country: United Kingdom
facility: GSK Investigational Site
city: Hull
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Oxford
country: United Kingdom
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.