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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002272 |
E.1.2 | Term | Anemia |
E.1.2 | System Organ Class | 100000004851 |
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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 administered threetimes weekly and Hgb at Day 29. |
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E.2.2 | Secondary objectives of the trial |
● Characterize the pharmacodynamic (PD) effect of GSK1278863 dose regimens on EPO, vascular endothelial growth factor (VEGF), hepcidin and red blood cells.
● Characterize the steady-state PK of GSK1278863 and major metabolites.
● Assess the safety and tolerability of GSK1278863 with three-times weekly administration for 29 days.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
AGE
1. ≥18 years of age, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Hemoglobin: Stable Hgb 9.0 - 11.5 g/dL (see Section 5.1).
3. 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.
4. 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%. NOTE: Only needs confirming at Day -28.
5. Stable ESA dose: Treated with the same ESA (epoetins or their biosimilars, or darbepoetin or methoxy PEG-epoetin beta) with total weekly dose varying by no more than 50% from 4 weeks prior to Day -28 through Day 1 (randomization).
6. Iron replacement therapy: Subjects may be on maintenance oral or IV iron supplementation. If subjects are on oral iron, then the type of iron and doses must not be changed for the 4 weeks prior to Day -28, during the screening phase, and through the 29 days of treatment. If subjects are on IV iron, then doses must be ≤100 mg/week, and doses must not be changed for the 4 weeks prior to Day -28, during the screening phase, and through the 29 days of treatment.
INFORMED CONSENT
7. Capable of giving signed informed consent as described in Section 10.2, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
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E.4 | Principal exclusion criteria |
1. Dialysis modality: Planned change from HD to peritoneal dialysis within study time period
2. Renal transplant: Planned for living-related or living-unrelated kidney transplant
3. High ESA dose: Epoetin dose of ≥360 IU/kg/week IV or ≥250 IU/kg/week subcutaneous (SC) or darbepoetin dose of ≥1.8 μg/kg/week IV or SC or methoxy PEG-epoetin beta dose of ≥2.2 μg/kg/week within the prior 8 weeks through Day1
4. Mircera: Administration of Mircera (methoxy PEG-epoetin beta) within 2 weeks prior to Day1 if subject is on a once-every-2-weeks schedule or within 4 weeks prior to Day1 if subject is on a once-every-4-weeks schedule
5. Myocardial infarction or acute coronary syndrome: Within 8 weeks prior to Screening through Day1
6. Stroke or transient ischemic attack: Within 8 weeks prior to Screening through Day1
7. Heart failure: Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Screening through Day1
8. QTcB: QTcB >500 msec or QTcB >530 msec in subjects with Bundle Branch Block. There is no QTc exclusion for subjects with a predominantly paced rhythm
9. 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 Day1
10. 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 through Day1.
11. Liver disease: Current liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asympt. 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
12. Major surgery: Major surgery (excl vasc. access surgery) within the 8 weeks prior to Screening, during the Screening phase, or planned during the study
13. Transfusion: Blood transfusion within the 8 weeks prior to Screening, during the Screening phase or an anticipated need for blood transfusion during the study
14. 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 Day1
15. Acute Infection: Clinical evidence of acute infection or history of infection requiring intravenous (IV) antibiotic therapy within the 4 weeks prior to Screening through Day1. NOTE: IV antibiotics as prophylaxis are allowed.
16. Malignancy: History of malignancy within the two years prior to Day -28 through to Day1 or currently receiving treatment for cancer, or has a known complex kidney cyst (i.e. Bosniak Category II F, III of IV) > 3cm. NOTE: The ONLY exception is squamous cell or basal cell carcinoma of the skin that has been definitively treated ≥ 8 weeks prior to Screening
17. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product
18. Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited (see Section 6.9.2 for details) from Screening until the Follow-up Visit
19. 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 Day1
20. Other conditions: Any other condition, clinical or laboratory abnormality, 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
21. Females ONLY: Does not meet the female eligibility criteria (Section 12.6 Appendix 6), is pregnant [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 Section 12.6.1.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
(To be verified on Day -28 only)
22. Vitamin B12: At or below the lower limit of the reference range (may rescreen in a min. of 8 weeks)
23. Folate: <2.0 ng/mL (4.5 nmol/L) (may rescreen in a min. of 4 weeks)
24. Ferritin: <100 ng/mL (<100 μg/L)
25. Transferrin saturation (TSAT): <20%. |
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E.5 End points |
E.5.1 | Primary end point(s) |
● Hgb change from baseline |
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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) |
● Maximum observed change from baseline in EPO
● Maximum observed % change from baseline in VEGF
● Change from baseline in hepcidin at Day 29
● Change from baseline in hematocrit, red blood cell (RBC) count, reticulocyte count and reticulocyte Hgb (CHr) at Day 29
● Descriptive PK summaries of GSK1278863 and major metabolites
● Incidence and severity of AEs and SAEs
● Reasons for discontinuation of investigational product
● Discontinuation for safety-related reasons, e.g., pre-specified stopping criteria or AE
● Absolute values and changes from baseline over time in laboratory parameters, ECGs and vital signs |
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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 | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Canada |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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Last Subject Last Visit (LSLV) |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |