| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia associated with chronic kidney disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anemia associated with chronic kidney disease |
|
| 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 | 17.1 |
| 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 |
|
| 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 ability of GSK1278863 to achieve mean Hgb response within the target range (9.0 to 10.5 g/dL) |
|
| E.2.2 | Secondary objectives of the trial |
-Characterize the ability of GSK1278863 to
achieve Hgb within the target range at week 12 and 24 (% in range).
-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
PK of GSK1278863 and metabolites
-Evaluate the GSK1278863 dose
adjustment scheme.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General criteria (Week -4 verification only)
1. Age: >or=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 11.6 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 study. Otherwise they must discontinue HRT to allow confirmation of post-menopausal 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 outlined in Section 11.6 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 criterion for subjects with a predominantly paced rhythm.
CKD-related criteria
4. CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 defined by eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula. The exception is that the Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) equation will be used for Japanese subjects from (or recruited at) Japan sites.
5. Hemoglobin: See Section 4.2 for details
a. Group 1 (rhEPO naïve): Baseline Hgb of 8.0-10.0 g/dL.
b. Group 2 (rhEPO users): Baseline Hgb of 9.0-10.5 g/dL.
6. rhEPO user:
Group 1: No current or prior rhEPO use within the past 8 weeks; e.g.,
epoetins (or their biosimilars), darbepoetin, Mircera (methoxy
polyethylene glycol epoetin beta), or their biosimilars.
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.
7. 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. |
|
| E.4 | Principal exclusion criteria |
Subjects are not eligible if they meet any of the following criteria.
CKD-related criteria
1. Dialysis: On dialysis or planning to initiate dialysis during the study
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
4. Mircera: Use of Mircera (methoxy polyethylene glycol epoetin beta) within the
prior 8 weeks through Day 1
5. 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 Laboratory test-based criteria (Week -4 verification only)
6. Vitamin B12: Below the lower limit of the reference range
7. Folate: <2.0 ng/mL (<4.5 nmol/L) (may rescreen in a minimum of 4 weeks
8. Ferritin: <40 ng/mL (<40 ug/L)
9. Transferrin saturation (TSAT): Outside of the reference range Cardiovascular disease-related criteria
10. Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to
Screening through Day 1
11. Stroke or transient ischemic attack: Within the 8 weeks prior to Week -4
Screening through Day 1
12. 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
- Symptomatic right heart failure diagnosed prior to Week -4 Screening through Day 1
13. Hypertension: Defined as DBP >100 mmHg or SBP>170 mmHg at Week -4 and reconfirmed at Day 1
14. Thrombotic Disease: History of thrombotic disease, except vascular access thrombosis within the 8 weeks prior to Week -4 Screening through Day 1
Other disease-related criteria
15. Ophthalmology disease: Meeting any ophthalmologic-related exclusion criteria determined at the Screening ophthalmology exam
16. Inflammatory disease: Active chronic inflammatory disease that could impact
erythropoiesis diagnosed prior to Week -4 Screening through Day 1
17. Hematological disease: Any hematological disease including those affecting platelets, white or red blood cells, coagulation disorders, or any other cause of anemia other than renal disease diagnosed prior to Week -4 Screening through Day 1
18. Liver disease: Current liver disease, known hepatic or biliary abnormalities or evidence at screening of abnormal liver function tests [alkaline phosphatase, 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.
19. Major surgery: Major surgery within the prior 8 weeks, during the Week -4 Screening phase or planned during the study
20. Transfusion: Blood transfusion within the prior 8 weeks, during the Week -4 Screening phase or an anticipated need for blood transfusion during the study
21. 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
22. 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
23. 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
Concomitant medication and other IP-related criteria
24. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product
25. 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
26. 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
General health-related criteria
27. Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk
28. Pregnancy or Lactation: Pregnant females as determined by positive urine 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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Hemoglobin concentration at Week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
•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.
•Number, frequency and timing of dose adjustments.
•Total cumulative and final dose.
•Number of Hgb excursions, Hgb cycles and dose cycles.
•Number (%) of subjects with at least one Hgb excursion.
•Number (%) of subjects with at least one Hgb cycle.
•Number (%) of subjects with at least one dose cycle.
•Time that dose is held because Hgb exceeded upper limits.
•Number (%) of subjects receiving additional therapies of blood transfusions, IV iron or rhEPO.
•Percentage of time within, below and above target range, between week 12 and 24
•Number (%) of subjects with Hgb in the target range at week 24
•Number (%) of subjects reaching pre-defined Hgb stopping criteria |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.8.1.4 | Double blind | No |
| 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 | 4 |
| 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 | 2 |
| 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 |
| Brazil |
| Canada |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United States |
|
| 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
|
| 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 patients' medical condition. |
|
| 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 |
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