Study to Evaluate the Safety and Efficacy of GSK1278863 in Recombinant Human Erythropoietin (rhEPO) Hyporesponsive Hemodialysis-dependent Chronic Kidney Disease Subjects With Anemia

Anemia Clinical Trial

Official title:

A 16-week, Phase 2a, Single-arm, Multi-center, Open-label Study to Evaluate the Safety and Efficacy of GSK1278863 After Switching From Recombinant Human Erythropoietin (rhEPO), in Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease Who Are Chronically Hyporesponsive to rhEPO

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02075463
• Other study ID #: 114837
• Status: Completed
• Phase: Phase 2
• First received: February 27, 2014
• Last updated: August 4, 2016
• Start date: June 2014
• Est. completion date: March 2016

Study information

• Verified date: June 2016
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The study will evaluate the ability of GSK1278863 to increase the hemoglobin (Hgb) concentration, or maintain it within the target range, and the safety and efficacy of GSK1278863 over 16 weeks of treatment, in hemodialysis-dependent subjects with anemia associated with chronic kidney disease who are chronically hyporesponsive to rhEPO. The data generated will inform dose requirements for any chronic rhEPO hyporesponsive hemodialysis-dependent subjects included in future clinical trials. The study consists of a 4-week rhEPO run-in period, a 16-week GSK1278863 treatment period and a 4-week Follow-up period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: March 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Hemodialysis (HD) frequency: Stable HD regimen of three to four times weekly for a minimum of 12 weeks. Note: The type and frequency of dialysis must be stable during the study. Isolated ultrafiltration sessions for the purposes of fluid removal are permitted.

• Dialysis Adequacy: Single-pool dialyzer clearance multiplied by dialyzer time divided by volume of distribution of urea (Kt/Vurea) of >=1.2 based on a historical value obtained within the prior month.

• rhEPO hyporesponsiveness: Historical and current intravenous (IV) rhEPO and Hgb values. Average epoetin alfa dose and Hgb level for three 4-week periods for a total of 12 weeks prior to Week -4, and during the 4 week run-in period, must be within the following ranges: average epoetin alfa dose >4000 and <=6000 units per session and Hgb >=8.0 and <=9.5 g/dL; average epoetin alfa dose >6000 and <=8000 units per session and Hgb >=8.0 and <=10.0 g/dL; average epoetin alfa dose >8000 and <=10000 units per session and Hgb >=8.0 and <=10.5 g/dL; and average epoetin alfa dose >10000 units per session and Hgb >=8.0 and <=11.0 g/dL.

• Absolute difference between the Hgb value at Week -4 and Week 0 (Day 1), must be <1.3 g/dL. Note: Subjects who do not meet the criteria after being rescreened twice, should not be entered into the GSK1278863 treatment period and should be withdrawn from the study.

• Age: >=18 years of age.

• Q-T Interval Corrected for Heart Rate (QTc): Bazett's Correction of QT Interval (QTcB) <470 msec or QTcB <480 milliseconds (msec) in subjects with bundle branch block. There is no corrected QT interval (QTc) inclusion criterion for a subject with a predominantly paced rhythm.

• Gender: Female and male subjects. Females: If of childbearing potential, must agree to use one of the approved contraception methods 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 amenorrea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 milliinternational units (MIU)/milliliter (mL) (23.0-116.3 international units (IU)/liter (L)) and estradiol <=10 picograms (pg)/mL (<=37 picomole (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 enrollment. 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.

Exclusion Criteria:

• Dialysis modality: Planned change in dialysis modality within the study time period.

• rhEPO: Use of methoxy polyethylene glycol epoetin beta or darbepoetin within the prior 8 weeks prior to Week -4.

• Renal transplant: Scheduled renal transplant.

• Transferrin saturation (TSAT): <20% on the most recent sample taken over the last 12 weeks.

• Ferritin: <100 nanograms (ng)/mL (<100 micrograms/L) on the most recent sample taken over the last 12 weeks.

• Vitamin B12: At or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).

• Folate: <2.0 ng/mL (<4.5 nanomoles (nmol)/L) (may rescreen in a minimum of 4 weeks).

• Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Week -4.

• Stroke or transient ischemic attacks (TIAs): Within the 8 weeks prior to Week -4.

• Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Week -4.

• Hypertension: Defined using pre-dialysis vitals (Week -4) of diastolic blood pressure >100 millimeters of mercury (mmHg) or systolic blood pressure >170 mmHg.

• Thrombotic disease: History of thrombotic disease (e.g., venous thrombosis such as deep vein thrombosis or pulmonary embolism, or arterial thrombosis such as new onset or worsening limb ischemia requiring intervention) within the 8 weeks prior to Week -4, except vascular access thrombosis.

• Inflammatory disease: Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease) diagnosed prior to Week -4.

• Hematological disease: Any hematological disease including those affecting platelets, white or red blood cells (e.g., antibody-mediated pure red cell aplasia, sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia), coagulation disorders (e.g., antiphospholipid syndrome, Protein C or S deficiency), or any other cause of anemia other than renal disease diagnosed prior to Week -4.

• 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 [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 with Hepatitis B or Hepatitis C are eligible provided these exclusions are not met.

• Major surgery: (excluding vascular access surgery) within the 8 weeks prior to Week -4, or planned during the study.

• Transfusion: Blood transfusion within the 8 weeks prior to Week -4, or an anticipated need for blood transfusion during the study.

• Gastrointestinal (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.

• Ophthalmology disease: History of proliferative retinopathy requiring treatment within the prior 12 months or macular edema requiring treatment.

• Acute infection: Clinical evidence of acute infection, evidence of underlying infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Week -4, and also through to Day 1. Note: IV antibiotics as prophylaxis are allowed.

• Malignancy: Subjects with a history of malignancy within the prior 5 years, who are 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.

• Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.

• Drugs and supplements: Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from Week -4 until the Follow-up Visit.

• Prior investigational product exposure: The subject has participated in a clinical trial and has received an experimental investigational product within the prior 30 days to Week -4.

• Life Expectancy: Life expectancy is considered by the investigator to be less than 6 months.

• Other conditions: Any other conditions, clinical or laboratory abnormality, or examination finding that the Investigator considers would put the subject at unacceptable risk, or an unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.

• Pregnancy and lactation: Pregnant females as determined by positive serum human chorionic gonadotrophin (hCG) test or women who are lactating at Week -4 or during the trial.

• Laboratory eligibility criteria will be assessed according to the central laboratory result for the screening samples

• Subjects who fail screening may be rescreened as soon as the investigator feels they may have subsequently become eligible. However, an individual subject may not be rescreened more than twice. There is no predetermined amount of time required to wait to rescreen a previously ineligible subject. Exceptions are those failing on Hgb or folate who may rescreen in 4 weeks and those failing for Vitamin B12 where rescreening may occur in 8 weeks.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anemia
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• GSK1278863
Film coated tablets containing 1 mg, 2 mg, 5 mg or 25 mg of GSK1278863
• Placebo
Matching placebo tablet for GSK1278863

Locations

Country	Name	City	State
United States	GSK Investigational Site	Amherst	New York
United States	GSK Investigational Site	Asheville	North Carolina
United States	GSK Investigational Site	Azusa	California
United States	GSK Investigational Site	Bethlehem	Pennsylvania
United States	GSK Investigational Site	Glendale	California
United States	GSK Investigational Site	Hollywood	Florida
United States	GSK Investigational Site	Houstan	Texas
United States	GSK Investigational Site	Knoxville	Tennessee
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Macon	Georgia
United States	GSK Investigational Site	Middlebury	Connecticut
United States	GSK Investigational Site	Paramount	California
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	Simi Valley	California
United States	GSK Investigational Site	Southgate	Michigan
United States	GSK Investigational Site	St Ann	Missouri
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of subjects demonstrating an increase in Hgb of =1 g/dL (if baseline Hgb is <9.5 g/dL), or =0.5 g/dL (if baseline Hgb is =9.5-<10 g/dL), or stay within the target range and do not drop by >0.5 g/dL (if baseline Hgb is =10 g/dL) at Week 16		Week 16	No
Secondary	Hgb change from baseline at Week 16		Week 16	No
Secondary	Percentage (%) of time within Hgb target range	The percentage of time a subject remains in Hgb target range (10.0 to 11.5 grams [g]/deciliter [dL]) whilst on treatment during the defined period	Week 12 to Week 16	No
Secondary	Percentage (%) of time below Hgb target range	The percentage of time a subject remains below Hgb target range whilst on treatment during the defined period.	Week 12 to Week 16	No
Secondary	Percentage (%) of time above Hgb target range	The percentage of time a subject remains above Hgb target range whilst on treatment during the defined period	Week 12 to Week 16	No
Secondary	Number (%) of subjects achieving at least a 1 g/dL increase in Hgb	Number of subjects achieving at least a 1 g/dL increase in Hgb as compared to baseline	Week 16	No
Secondary	Number (%) of subjects with Hgb in the target range	Number of subjects with Hgb in target range	Week 16	No
Secondary	Number (%) of subjects reaching predefined Hgb stopping criteria	Number of subjects reaching pre-defined Hgb study medication discontinuation criteria.	Up to Week 16	No
Secondary	Change from baseline in hepcidin		Week 16	No
Secondary	Change from baseline in ferritin		Week 16	No
Secondary	Change from baseline in transferrin		Week 16	No
Secondary	Change from baseline in transferrin saturation		Week 16	No
Secondary	Change from baseline in total iron		Week 16	No
Secondary	Change from baseline in total iron binding capacity		Week 16	No
Secondary	Change from baseline in reticulocyte hemoglobin content		Week 16	No
Secondary	Change from baseline in mean corpuscular volume (MCV)		Week 16	No
Secondary	Change from baseline in mean corpuscular hemoglobin (MCH)		Week 16	No
Secondary	Change from baseline in hematocrit		Week 16	No
Secondary	Change from baseline in red blood cells		Week 16	No
Secondary	Change from baseline in reticulocyte number		Week 16	No
Secondary	Maximum observed change from baseline in vascular endothelial growth factor (VEGF).		Week 16	No
Secondary	Maximum observed change from baseline in erythropoietin (EPO).		Week 16	No
Secondary	Mean final dose of GSK1278863 administered.		Up to Week 16	No
Secondary	Population Pharmacokinetics		Day 1, Week 4 and Week 12	No