Anemia in chronic Kidney disease (Oral Doses of GSK1278863A in anaemic pre-dialysis and hemodialysis-dependent patients)

Phase 2

Completed

Conditions: Health Condition 1: null- Anemia in Pre-dialysis and Hemodialysis-dependent Chronic Kidney Disease Patients

Registration Number: CTRI/2010/091/000282

Lead Sponsor: GlaxoSmithKline LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 140

Inclusion Criteria

A patient will be eligible for inclusion in this study only if all of the following criteria apply:

1. Male or female between 18 and 85 years of age inclusive, at the time of signing the informed consent.

2. A male or female is eligible to enroll and participate in this study if he/she:

a. (Part 1) has Moderate to Severe Renal Impairment (equivalent to NKF KDOQI Stage 3 or 4, not receiving dialysis) as determined by estimated Glomerular Filtration Rate (eGFR) calculated by the abbreviated MDRD equation, and not expected to go on dialysis until ≥ 8 weeks after first administration of investigational product. Stage 5, non-dialysis patients with eGFR of 10 15 mL/min per 1.73 m2 will also be eligible for Part 1 on a case-by-case basis.

b. (Part 2) has Severe Renal Impairment and has been on stable hemodialysis treatment for 1 month prior to Screening (subjects with planned transition to hemodialysis) or 3 months prior to Screening (subjects emergently placed on hemodialysis). These subjects are equivalent to NKF KDOQI Stage 5.

c. otherwise healthy or considered clinically stable with respect to underlying renal impairment and with respect to underlying/chronic disease as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.

d. has clinical laboratory test results that are considered clinically stable in the opinion of the principal investigator, especially if the clinical abnormality or laboratory parameter is deemed associated with the patient?s underlying renal impairment.

3. Meets the following erythropoiesis stimulating agent (ESA) criteria:

a. The patient is ESA naÃ¯ve

b. If the patient has a scheduled ESA interval which is ≤ 7 days, ESA treatment must be discontinued for at least 7 days

c. If the patient has a scheduled ESA interval which is > 7 days, ESA treatment must be discontinued for at least that scheduled interval length (eg discontinued ≥ 14 days for a scheduled 14 day ESA interval)

AND

The patient will not resume ESA treatment until completion of the Follow-up Visit (Day 57).

4. Has a hemoglobin value:

a. For ESA naÃ¯ve patients: ≤11.0 g/dL

b. For patients receiving ongoing ESA treatment: ≤11.5 g/dL at Screening with a re check value of ≤11.0 g/dL after appropriate ESA discontinuation according to Inclusion 3 and prior to commencing study drug dosing.

5. Has serum ferritin at Screening:

a. ≥40 μg/L with the absence of microcytic or hypochromic RBCs (regardless of transferrin saturation %)

b. 25-39 μg/L with transferrin saturation % ≥20% (fraction saturation ≥0.20) and the absence of microcytic or hypochromic RBCs

6. Has Vitamin B12 and folate above the lower limit of normal at Screening

7. A female patient is eligible to participate if she is:

a. of childbearing potential, and must agree to use one of the contraception methods in Section 8.1.1. This criterion must be followed from the time of Screening until completion of the Follow-up Visit (Day 57).

b. of 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 ca

Exclusion Criteria

A patient will not be eligible for inclusion in this study if any of the following criteria apply:
1. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months prior to Screening and one of the following:
? evidence of autoimmune anemia
? prior anti-viral therapy
? evidence of liver damage
2. A positive test for HIV antibody.
3. A pre-study drug screen that is positive due to drug use not associated with a current medication prescription. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
4. A value at Screening is greater than 1.5 times the upper limit of reference range for AST, ALT, or direct bilirubin.
5. Hemolysis/hemolytic anemia or active bleeding/blood loss
6. Androgen therapy within 8 weeks prior to first dose of study drug (Day 1).
7. Red blood cell transfusion within 90 days prior to first dose of study drug (Day 1).
8. Iron replacement therapy:
a. Intravenous iron replacement therapy within 30 days prior to the first dose of study drug on Day 1 until completion of the Follow-up Visit (Day 57).
b. Oral iron replacement therapy started or discontinued within 30 days prior to Screening. (Patients currently receiving oral iron replacement therapy which was initiated at least 30 days prior to Screening, will be allowed to continue their oral iron replacement therapy during the study and should not discontinue the therapy until after completion of all study drug doses and Day 29 assessments.)
9. History of thrombosis defined as deep vein thrombosis, stroke, pulmonary embolism or other thrombosis related condition within 1 year prior to Screening.
10. Known active decompensated hyperparathyroidism or history of bone marrow fibrosis.
11. Systemic hematologic disease, including, but not limited to sickle cell disease, hemosiderosis, hemochromatosis, myelodysplastic syndrome, hematologic malignancy, myeloma
12. Post-renal transplantation patients with functioning transplant. (Failed transplant subjects back on hemodialysis are eligible).
13. Acute peptic ulcer disease or history of chronic rectal bleeding.
14. History of malignancy tumor within 5 years prior to Screening or are receiving medication for cancer. Non-melanoma skin cancer within the past 5 years that has been definitively removed is allowed.
15. Patients 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 the study drugs. 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 Gilberts syndrome.
16. Active infection or acute inflammatory disease as determined by clinical assessment.
17. Class III heart failure with evidence of recent progression (worsening dyspnea, hospitalization within 2-3 months for symptoms, etc), or Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
18. Uncontrolled hypertension (diastolic BP >100 mmHg or systolic BP >160 mmHg at Screening)
19. Myocardial infarction or acute coronary syndrome within 1 year prior to Screening.
20. Histo

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
1.Rate of response for patients achieving the target increases from baseline of hemoglobin levels, hemoglobin actual values, rate of rise, maximum change from baseline, and rate of decline following stopping of dosing <br/ ><br>2. adverse events reporting, clinical safety laboratory tests (hematology, chemistry, and, when obtainable, urinalysis), vital signs (blood pressure and heart rate), ECG, and clinical monitoring/observationTimepoint: Screening, Day 1, 4, 8, 15, 22, 29, 36, 57

Secondary Outcome Measures

Name	Time	Method
1.AUC(0-â??), AUC(0-Ï?), Cmax, tmax and t1/2, on Days 1, 15, and 22 through sparse sampling/population pharmacokinetics in subset of patients. <br/ ><br>2. Actual values and change from baseline for erythropoietin, absolute and percent reticulocytes, hematocrit, and total RBCs. <br/ ><br>3. Actual values and change from baseline for VEGF, hepcidin, TIBC, transferrin saturation (%), serum iron, serum ferritin, and fetal hemoglobin, as appropriate (also fetal hemoglobin as a percent of total hemoglobin)Timepoint: Day 1, 4, 8,15, 22, 29 and 57