| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anaemia associated with chronic kidney disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anaemia 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 | 14.1 |
| 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 |
| Estimate the relationship between dose of GSK1278863 and hemoglobin (Hgb) response following switching from a stable dose of rhEPO in subjects undergoing HDD. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
• Characterize the effect of GSK1278863 on additional measures of Hgb response.
• Characterize the effect of GSK1278863 on EPO, measures of iron metabolism and utilization (hepcidin, ferritin, transferrin, transferrin saturation, total iron, total iron binding capacity (TIBC)), a measure of inflammation (high sensitivity C-Reactive Protein; hsCRP) and vascular endothelial growth factor (VEGF).
• Characterize the steady-state population PK of GSK1278863 and relevant metabolites.
•Assess the safety and tolerability of GSK1278863 following QD administration for 4 weeks. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria as verified at Screening (Week -1):
1. Age and weight:>/=18 years of age and >/= 45 kg (weight post-dialysis).
2. Hemodialysis:
a. On three times weekly hemodialysis for at least 8 weeks, irrespective of eGFR values and stage of CKD.
b. A single-pool Kt/Vurea of >/=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%.
3. rhEPO use: Using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses that varied by no more than 50% during the prior 4 weeks (i.e., maximum vs. minimum total weekly doses </=50%).
4. Lab Inclusions:
a. Hgb concentrations 9.5-12.0 g/dL (inclusive) as described in Section 4.2.
b. Vitamin B12 above the lower limit of the reference range (may rescreen in two months).
c. Folate: >/= 2.0 ng/mL (may rescreen in one month).
d. Ferritin: >/=40 ng/mL with the absence of microcytic or hypochromic RBCs.
e.Transferrin saturation (TSAT): Within the reference range.
5.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).
6.QTc: QTcB <470 msec or QTcB <480 msec in subjects with bundle branch block obtained at Screening Visit (based on Central Reader’s interpretation).
NOTE: Two additional ECGs are required if ECG interpretation indicates possible prolonged QTc as defined by QTcB value on the initial tracing. The average of these three ECGs (based on the Central Reader’s interpretation) will be used to determine eligibility.
7.Females: Eligible to participate if she is:
•Of childbearing potential, and must agree to use one of the approved contraception methods outlined in Section 6.3.5.1 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 amenorrea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)>40MIU/ml and estradiol <40pg/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 enrolment. For most forms 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.
8. Males: Must agree to use one of the approved contraceptive methods as outlined in Section 6.3.5.2 from the time of Screening until completion of the Follow-up Visit. |
|
| E.4 | Principal exclusion criteria |
CKD-related criteria
1.Dialysis modality: On peritoneal dialysis OR planned change in dialysis modality within the study time period.
2.rhEPO Hyporesponders: As defined by an epoetin dose of >/=360 IU/kg/week IV or darbepoetin dose of >/=1.8 µg/kg/week IV within the prior 8 weeks.
3.Renal transplant anticipated or scheduled within the study time period or subjects with a functioning renal transplant.
4. Mircera or Peginesatide: Current or prior use (within the prior 8 weeks) of Mircera (methoxy polyethylene glycol epoetin beta) OR peginesatide.
5.Lab Exclusions:
a.Total CPK: >5x the upper limit of the reference range.
b.HIV: Positive HIV antibody.
6.Prior CV Events:
a.History of myocardial infarction or acute coronary syndrome within the prior 6 months.
b.History of stroke or transient ischemic attacks (TIAs) within the prior 6 months.
7.Heart failure: Class III/IV heart failure, (NYHA) functional classification system.
8.Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or lack of treatment
9.Thrombotic Disease: History of thrombotic disease, or other thrombosis related condition except shunt thrombosis 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.
11.Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis.
12.Haematological disease: Any haematological disease including those affecting platelets, the coagulation disorders or red blood cells 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, 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.
NOTE: Those Hepatitis C positive are eligible provided these laboratory exclusions are not met.
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 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).
NOTE: IV antibiotics as prophylaxis are allowed.
18.Malignancy: History of malignancy within the prior 5 years or are receiving treatment for cancer or those with a strong family history of cancer, with the exception of squamous cell or basal cell carcinoma of the skin that has been definitively treated.
19.Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months or macular edema requiring treatment.
20.Severe reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (refer to GSK1278863 IB).
21.Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Screening until the Follow-up Visit.
22.Androgens: New androgen therapy or changes to pre-existing androgen regimen within the prior 12 weeks.
23.Prior investigational product exposure: The Subject has participated in a clinical trial and has received an experimental investigational product within the prior 30 days.
General health-related criteria
24.Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.
25.Other Conditions: Any condition which in the investigator’s opinion should exclude the subject from participating in the study.
26.Pregnancy or Lactation: Pregnant females as determined by positive serum hCG test OR women who are lactating at Screening or during the trial.
Other Eligibility Criteria Considerations
Laboratory eligibility criteria will be assessed according to the central laboratory result for the screening samples.
Subjects who screen fail may be rescreened once if they may subsequently become eligible. Exceptions are those failing on Hgb or folate who may rescreen in one month and those failing for Vitamin B12 where rescreening may occur in two months. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Modelled Hgb change from baseline over 4 weeks of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 4 weeks after starting treatment |
|
| E.5.2 | Secondary end point(s) |
•Endpoints to describe Hgb variability over the 4 weeks include:
-Within subject standard deviation (SD).
-Residual SD - derived from a regression model.
-Time spent with Hgb within range (where range will be defined as ±0.5 g/dL and ±1 g/dL from baseline Hgb).
-Area Under the Hgb Change versus time Curve (AUC) – using change from baseline.
-Number of subjects who have reached Hgb stopping criteria.
•Evaluation of change in markers of iron metabolism and utilization (hepcidin, ferritin, transferrin, transferrin saturation, total iron, TIBC), and a measure of inflammation (hsCRP).
•Evaluation of change in EPO, hematocrit, RBC, reticulocytes, VEGF plasma concentrations.
•Population PK parameters of GSK1278863 and relevant metabolites.
•Discontinuation for safety-related reasons, e.g. pre-specified stopping criteria or AE.
•Incidence and severity of AEs and SAEs.
•Absolute values and changes from baseline over time in laboratory parameters, ECGs and vital signs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 4 weeks of treatment as well as the timecourse (Week 1, 2 and 3). |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Double blind for GSK1278863 arms and open for rhEPO arm |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Denmark |
| Germany |
| Norway |
| Sweden |
| United States |
|
| 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
|
|
| 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 | 5 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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