E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anemia associated with chronic kidney disease (CKD) |
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E.1.1.1 | Medical condition in easily understood language |
Anemia associated with chronic kidney disease (CKD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
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 steady-state PK of GSK1278863 and metabolites
(GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), GSK2531398 (M6), GSK2531401 (M13) in ESRD subjects undergoing peritoneal dialysis. |
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E.2.2 | Secondary objectives of the trial |
Evaluate the safety and tolerability of GSK1278863 in ESRD subjects
undergoing peritoneal dialysis
Characterize the peritoneal dialysis clearance of GSK1278863 and metabolites in ESRD subjects undergoing peritoneal dialysis
Characterize the plasma profile of erythropoietin and hepcidin after repeat-dose administration of GSK1278863 in ESRD subjects undergoing peritoneal dialysis |
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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:
Safety
1. Satisfactory medical evaluation based upon medical history, medication history, physical examination, and clinical laboratory data obtained at the Screening visit. The determination of clinical significance will be made by the Investigator and the GSK Medical Monitor and will require that the finding is unlikely to introduce
additional risk factors or interfere with the study procedures, or the integrity of the study.
2. QTc < 470 msec OR QTc < 480 msec in subjects with Bundle Branch Block. These should be based on average of triplicate values obtained over a brief recording period at Screening and on Day -1 and the single reading on Day 17. The same QT correction formula should be used to determine inclusion and discontinuation for any individual subject throughout the study.
3. Vitamin B12 and folate above the lower limit of normal at Screening.
4. AST, ALT, and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Efficacy
5. A subject is eligible to enroll and participate in this study if he/she has ESRD and is on peritoneal dialysis for at least 2 months with estimated minimal residual kidney function (average urine output < 100 mL/daily) with stable Kt/V urea > 1.7 weekly.
6. No history of peritoneal dialysis-associated peritonitis, peritoneal catheter tunnel (exit site) infection or leakage for at least 3 months before study.
7. Meets the following erythropoiesis stimulating agent (ESA) criteria:
- Is ESA naive (i.e., no ESA use within the previous 12 weeks of screening)
OR
- Agrees to discontinue ESA (if currently using ESA) for at least 7 days prior to first dose of GSK1278863 until completion of Follow-up visit.
a. If the subject has a scheduled ESA interval which is ≤ 7 days, ESA
treatment must be discontinued for at least 7 days prior to first dose of
GSK1278863
b. If the subject has a scheduled ESA interval which is > 7 days, ESA
treatment must be discontinued for at least the scheduled interval
length (e.g., if ESA interval is 14 days, then ESA must be discontinued
for > 14 days) prior to the first dose of GSK1278863
8. Has a hemoglobin value:
- For ESA naïve subjects: <10.0 g/dL
- For subjects receiving ongoing ESA treatment: Smaller than or equal to 11.0 g/dL at Screening.
Other
9. Subjects who are ≥ 18 years of age at the time of Screening.
10. A female subject is eligible to participate if she is of:
- Childbearing potential, and agrees to use one of the contraception methods described in the protocol. This criterion must be followed from the time of Screening until completion of the Follow-up Visit.
- Non-childbearing potential, defined as pre-menopausal females with a
documented tubal ligation or hysterectomy; 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 ≤10 pg/mL (or ≤37 pmol/L) is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described in the protocol 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
enrollment. For most forms of HRT, at least 2 months 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.
11. Body weight > 45 kg and < 140 kg at Screening.
12. The subject is mentally and legally able to comply with the requirements and restrictions of the protocol and has provided signed informed consent prior to participation in any protocol-specific procedures, including Screening procedures. |
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E.4 | Principal exclusion criteria |
Safety
1. A positive test for HIV antibody.
2. Uncontrolled hypertension (diastolic BP >100 mmHg or
systolic BP >170 mmHg) at Screening.
3. History of drug abuse or dependence within 6 months of the study.
4. History of sensitivity to GSK1278863, or its components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.
5. History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
6. History of thrombosis defined as deep vein thrombosis, stroke, pulmonary embolism or other thrombosis related condition within 3 months prior to Screening.
7. History of myocardial infarction or acute coronary syndrome within 3 months prior to Screening.
8. History of stroke or transient ischaemic attack within 3 months prior to Screening.
9. Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of GSK1278863. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include gastrointestinal
bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn’s disease, ulcerative colitis, or celiac sprue. Examples of conditions that could interfere with hepatic function include Gilbert’s syndrome.
10. Evidence of active peptic, duodenal or esophageal ulcer disease at Screening OR history of clinically significant GI bleeding within 3 months prior to Screening.
11. Subjects with chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).
12. Subjects with a history of symptomatic right heart failure.
13. Subjects with Class III or Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
14. Active malignancy or diagnosis of malignancy within 5 years prior to Screening (excluding successfully treated basal or squamous cell carcinoma).
15. History of proliferative vascular eye disease (e.g., choroidal or retinal disease, such as neovascular age-related macular degeneration, proliferative diabetic retinopathy or macular edema) based upon having had an ophthalmologic exam within 12 months prior to Screening.
16. Pregnant females as determined by positive serum -hCG test at Screening or Day -1.
17. Lactating females.
18. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period prior to first dose.
19. Consumption of red wine, grapefruit (juice), blood orange (juice), star fruit, onions, kale, broccoli, green beans, or apples from 7 days prior to the first dose of investigational product until the Follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor this will not interfere with the study procedures and compromise subject safety.
20. Use or planned use of any prescription or non-prescription drugs that are prohibited (see Section 5.10.2) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of GSK1278863 until completion of the follow-up visit, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or
compromise subject safety.
21. The following medications are specifically prohibited for the duration of the study (from Screening to the follow-up visit at the end of the study):
- Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of low dose (≤325 mg/day) aspirin/acetylsalicylic acid. Occasional NSAID use is permitted (refer to Section 5.10.2.2).
- Immunosuppressant drugs and drugs used to treat malignancies (including corticosteroids at doses >10 mg prednisolone per day or equivalent) within 2 weeks of first dose of GSK1278863.
Note: Failed transplant subjects back on peritoneal dialysis are eligible for participating in this study but should not be on immunosuppressive medications within 3 months prior to Screening.
22. The subject has participated in a clinical trial and has received an experimental investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Efficacy
23. The values of ferritin and transferrin within 3 months prior to Screening are:
a. transferrin saturation < 20%
b. serum ferritin < 100 μg/L
Please refer to the protocol P22 for further details. |
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E.5 End points |
E.5.1 | Primary end point(s) |
AUC(0-τ), AUC(0-∞) (Day 1 only), and Cmax of GSK1278863 and metabolites |
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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) |
• Subject incidence of treatment-emergent adverse events, including clinically-significant changes in physical exams, laboratory safety tests, ECG and vital signs
• Peritoneal dialysis clearance, tmax and t½ of GSK1278863 and metabolites
• Accumulation ratio and time invariance ratio (as data permit) of GSK1278863 and metabolites
•Erythropoietin and hepcidin plasma concentrations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Adverse events: Day 1 to 17
• Laboratory safety tests, ECG, Vital signs: Day 1 & 17
• Peritoneal dialysis clearance, tmax and t½ of GSK1278863 and metabolites: Day 1 & 14
• Accumulation ratio and time invariance ratio (as data permit) of GSK1278863 and metabolites: Day 14
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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 | No |
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 | 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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
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 |
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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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LVLS
A completed subject is one who has completed all phases of the study including the follow-up visit.
The end of the study is defined as the last subject’s last visit. |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |