E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anemia associated with chronic kidney disease |
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E.1.1.1 | Medical condition in easily understood language |
Anemia associated with chronic kidney disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 100000004857 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Characterize the dose-response relationship
between GSK1278863 and Hgb at Week 4. |
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E.2.2 | Secondary objectives of the trial |
-Characterize the ability of GSK1278863 to
achieve Hgb within the target range (10.0 to
11.5 g/dL).
-Characterize the effect of GSK1278863 on
measures of iron metabolism and utilization, on indices of hematopoiesis, EPO and on Vascular Endothelial Growth Factor (VEGF)
-Characterize the steady-state population
pharmacokinetic (PK) of GSK1278863 and
metabolites.
-Assess the safety and tolerability of GSK1278863 following once daily (QD) administration for 24 weeks.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects are eligible if they meet all of the inclusion criteria below. Generalcriteria (Week -4 verification only)
1.Age: >18 years of age.
2.Gender: Female and male subjects.
• Females: If of childbearing potential, must agree to use one of the approved contraception methods as outlined in Section 11.5 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 [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 IU/L and estradiol <or= 10 pmol/L 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 stud Otherwise they must discontinue HRT to allow confirmation of post-menopaus status prior to study enrolment. For most forms of HRT, at least 2 weeks must 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.
• Males: must agree to use one of the approved contraceptive methods as outline in Section 11.5 from the time of Screening until completion of the Follow-up Visit.
3. QTc: QTcB <470 msec or QTcB <480 msec in subjects with bundle branch block.
There is no QTc inclusion criterion for a subject with a predominantly paced rhythym
CKD-relatedcriteria
4. Dialysis frequency: On hemodialysis (HD) three to five times weekly for at least weeks prior to Week -4 Screening through Week 4.
NOTE: Combination methods including hemofiltration (HF) or ultrafiltration (UF) with HD are allowed. However, the type of dialysis (HD, hemodiafiltration (HDF) or (UF) should not change during the study.
5. Dialysis adequacy: A single-pool Kt/Vurea of >or=1.2 based on a historical value obtained within the prior month 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%.
NOTE: Only needs confirming at Week -4.
6. Hemoglobin: Baseline Hgb of 9.0-11.5 g/dL as outlined in Section 4.2 (may rescreen in a minimum of 2 weeks).
7. Stable rhEPO dose: Using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses varying 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.
8. Iron replacement therapy: Subjects may be on stable maintenance oral or IV (<or= 100mg/week) iron supplementation. If subjects are on oral or IV iron, then doses mus stable for the 4 weeks prior to Week -4, during the screening phase, and through the first 4 weeks after Randomization. |
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E.4 | Principal exclusion criteria |
Subjects are not eligible if they meet any criteria below.
CKD-related criteria
1.Dialysis modality:Planned change from HD to peritoneal dialysis within the study time period.
2.Renal transplant:Pre-emptive or scheduled renal transplant.
3.High rhEPO dose:An epoetin dose of >or=360 IU/kg/week IV or darbepoetin dose of >or=1.8 µg/kg/week IV within the prior 8 weeks through Day 1 (randomization).
4.Mircera:Use of Mircera (methoxy polyethylene glycol epoetin beta) within the prior 8 weeks through Day 1 (randomization).
Laboratory test-based criteria (Week -4 verification only)
5.Vitamin B12: At or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
6.Folate: <2.0 ng/mL (<4.5 nmol/L) (may rescreen in a minimum of 4 weeks).
7.Ferritin:<100 ng/mL (<100 ug/L).
8.Transferrin saturation (TSAT):Outside of the reference range. Cardiovascular disease-related criteria
9.Myocardial infarction or acute coronary syndrome:Within the 8 weeks prior to Screening through Day 1 (randomization).
10.Stroke or transient ischemic attack:Within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
11.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).
12.Hypertension:Defined using pre-dialysis vitals (Week -4, Day 1) of DBP >100 mmHg or SBP >170 mmHg.
13.Thrombotic disease:History of thrombotic disease, except vascular access thrombosis, within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
Other disease-relatedcriteria
14.Ophthalmology disease:Meeting any ophthalmologic-related exclusion criteria determined at the Screening ophthalmology exam as outlined in Section 11.6.
15.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).
16.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 or any other cause of anemia other than renal disease diagnosed prior to Week -4 Screening through Day 1 (randomization).
17.Liver disease:Current liver disease, known hepatic or biliary abnormalities or evidence at Screening of abnormal liver function tests or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
18.Major surgery:Major surgery (excluding vascular access surgery) within the prior 8 weeks, during the Week -4 Screening phase or planned during the study.
19.Transfusion:Blood transfusion within the prior 8 weeks, during the Week -4 Screening phase or an anticipated need for blood transfusion during the study.
20.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).
21.Acute infection: Clinical evidence of acute infection or history of infection requiring intravenous (IV) antibiotic therapy within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
22.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).
Concomitant medication and other IP-related criteria
23.Severe allergic reactions:History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product
24.Drugs and supplements:Use of any prescription or non-prescription drugs or dietary supplements that are prohibited (see Section 5.7.2 for details) from Week -4 Screening until the Follow-up Visit.
25.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).
Generalhealth-relatedcriteria
26.Other Conditions:Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk.
27.Pregnancy or Lactation:Pregnant females as determined by positive serum hCG test OR women who are lactating at Week -4 Screening or during the trial.
Refer to protocol (page 27) for other Eligibility Criteria Considerations
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E.5 End points |
E.5.1 | Primary end point(s) |
Hemoglobin change from baseline at Week 4 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Hgb concentration at Week 24
•Percentage of time within, below, and above target range between Week 20 and 24
•Number (%) of subjects with Hgb in the target range at Week 24
•Number (%) of subjects reaching pre-defined Hgb
stopping criteria
•Change from baseline in hepcidin, ferritin, transferrin, transferrin saturation, total iron, total iron binding capacity (TIBC), reticulocyte Hgb (CHr), %hypochromic red blood cells (RBCs) at Week 24
•Change from baseline in hematocrit, RBC, reticulocyte number at Week 24
•Maximum observed change from baseline in EPO
•Maximum observed change from baseline in VEGF
•Population plasma PK parameters of GSK1278863 and metabolites
•Incidence and severity of adverse events (AE)s and serious AEs (SAEs)
•Reasons for discontinuation of study drug
•Discontinuation for safety-related reasons, e.g. pre-specified stopping criteria or AE
•Absolute values and changes from baseline in laboratory parameters, systolic pulmonary artery pressure (sPAP) left ventricular ejection fraction (LVEF), ophthalmology assessments, and vital signs
•Preliminary assessment of major adverse cardiovascular events (MACE) and other cardiovascular (CV) events
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Double blind for GSK1278863 arms and open for Control arm from Week 4 onwards |
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E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Japan |
Korea, Republic of |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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GSK is not providing specific post-study treatment.
The investigator is responsible for ensuring that consideration has been given to the post-study care of the patient’s medical condition |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |