4 Week Correction Study in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Not Undergoing Dialysis

NCT ID: NCT01587898

Last Updated: 2017-11-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 72 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-17
• Study Completion Date: 2013-05-07

Brief Summary

This is a four-week Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to evaluate the safety, efficacy and pharmacokinetics of GSK1278863 in approximately 68 subjects with anemia associated with chronic kidney disease who are not taking rhEPO and are not undergoing dialysis. The range of Hgb values for study eligibility is 8.5-11.0 g/dL. Eligible subjects will be randomized in equal proportions to receive once daily (QD) placebo or GSK1278863 0.5 mg, 2 mg or 5 mg in a double-blind fashion.

Detailed Description

This is a four-week Phase IIa, randomized, double-blind, placebo-controlled, parallel-group, multi-center study to evaluate the safety, efficacy and pharmacokinetics of GSK1278863 in approximately 68 subjects with anemia associated with chronic kidney disease who are not taking rhEPO and are not undergoing dialysis. The study consists of a screening phase of up to 2 weeks, a 4-week treatment phase and a 2-week follow-up phase. The range of Hgb values for study eligibility is 8.5-11.0 g/dL. Eligible subjects will be randomized in equal proportions to receive once daily (QD) placebo or GSK1278863 0.5 mg, 2 mg or 5 mg in a double-blind fashion. Study treatment will be stopped if Hgb values fall outside of the range pre-specified in the protocol.

This study aims to estimate the relationship between dose of GSK1278863 and Hgb response for correcting anemia in non-dialysis subjects with CKD who are not taking rhEPO (NDD). In addition, the study will characterize the effect of GSK1278863 on various pharmacokinetic/pharmacodynamic (PK/PD) markers, and will investigate the safety and tolerability of GSK1278863.

An early interim analysis of the Hgb data is planned after approximately 20 subjects from cohort 1 have completed 3 weeks of treatment. Depending upon the interim findings, a second cohort of subjects may be added to investigate an additional GSK1278863 dose arm. Recruitment to the first cohort will continue during the interim analysis.

A second interim analysis is planned after approximately 48 subjects from cohort 1 have completed 4 weeks treatment. The purpose of this interim is three-fold, to investigate whether a second cohort of subjects may be added, to facilitate early development of dose-response and PK/PD statistical models, and to generate interim results to facilitate design and dosing decisions for the next trial.

Subject completion is defined as completion of all study phases including the follow-up phase.

Conditions

Anaemia

Keywords

Anemia; Prolyl hydroxylase inhibitor; Hemoglobin; Chronic kidney disease; pharmacokinetics; recombinant human erythropoietin; GSK1278863

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

0.5mg GSK1278863

Once daily

Group Type: EXPERIMENTAL

GSK1278863

Intervention Type: DRUG

Tablet

2mg GSK1278863

Once daily

Group Type: EXPERIMENTAL

GSK1278863

Intervention Type: DRUG

Tablet

5mg GSK1278863

Once daily

Group Type: EXPERIMENTAL

GSK1278863

Intervention Type: DRUG

Tablet

Placebo

Once daily

Group Type: EXPERIMENTAL

Placebo

Intervention Type: OTHER

Tablet

Interventions

GSK1278863

Tablet

Intervention Type: DRUG

Placebo

Tablet

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Age and weight: >/= 18 years of age and >/= 45 kg.

2. Not routinely undergoing dialysis, regardless of the modality (either hemodialysis or peritoneal dialysis) or dialysis planned during the time the subject would be enrolled in the study.

3. No current or prior rhEPO use within the past 7 weeks; e.g., epoetins (or their biosimilars), darbepoetin, Mircera (methoxy polyethylene glycol epoetin beta), peginesatide or their biosimilars..

4. KDOQI CKD stages 3/4/5 defined by eGFR using the Modification of Diet for Renal Disease (MDRD).

5. Hgb: Hgb concentrations 8.5-11.0 g/dL (inclusive) as outlined in Section 4.2.

6. Vitamin B12: Above the lower limit of the reference range (may rescreen in 2 months).

7. Folate: >/=2.0 ng/mL at Screening. May rescreen in a month.

8. Ferritin: >/=40 ng/mL with the absence of microcytic or hypochromic RBCs.

9. TSAT within the reference range.

10. 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).

11. QTc: QTcB <470 msec or QTcB <480 msec in subjects with bundle branch block obtained at Screening Visit, based on Central Reader's interpretation.

12. Females: Eligible to participate if she is of childbearing potential, and must agree to use 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 of hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)>40 MIU/ml and estradiol <40 pg/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 enrollment. For most types 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.

13. Males: Must agree to use approved contraceptive methods from the time of Screening until completion of the Follow-up Visit.

Exclusion Criteria

1. Dialysis: Planning to initiate dialysis during the study or who have a high potential for initiating dialysis during study participation.

2. Renal transplant: Renal transplant anticipated or scheduled within the study time period or subjects with a functioning renal transplant.

3. Total CPK: >5x the upper limit of the reference range.

4. HIV: Positive HIV antibody.

5. History of myocardial infarction or acute coronary syndrome within the prior 6 months.

6. History of stroke or TIAs.

7. Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.

8. Hypertension: Poorly controlled hypertension, whether due to inadequate treatment, or lack of treatment, defined as DBP >100 mmHg or SBP>160 mmHg.

9. 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), or other thrombosis related condition) 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 (e.g., significant heart failure or lung disease requiring supplemental oxygen, or those with connective tissue diseases).

11. Inflammatory disease: Chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosis, rheumatoid arthritis, celiac disease).

12. Hematological disease: Any hematological disease including those affecting platelets, the coagulation disorders (e.g., Protein C or S deficiency) or red blood cells (e.g. sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia) 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, ALT or 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.

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 active 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).

18. Malignancy: History of malignancy within 5 years of Screening or are receiving treatment for cancer or those with 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.

19. Hyperparathyroidism: Clinically significant hyperparathyroidism in the opinion of the Investigator, including subjects with parathyroid hormone (PTH) values ≥600 pg/mL.

20. Eyes: History of proliferative retinopathy requiring treatment within the prior 12 months, or macular edema requiring treatment.

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

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

23. Androgens: New androgen therapy or changes to pre-existing androgen regimen within prior 12 weeks.

24. Prior investigational product exposure: The subject has participated in a clinical trial and has received an experimental investigational product within prior 30 days.

25. Protocol compliance: Unwillingness or inability to follow the procedures, or lifestyle and/or dietary restrictions outlined in the protocol.

26. Other conditions: Any condition which in the investigators opinion should exclude the subject from participating in the study.

27. Pregnancy and lactation: Pregnant females as determined by positive urine hCG test, OR women who are lactating at Screening or during the trial.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

PPD Development, LP

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Azusa, California, United States

GSK Investigational Site

Bakersfield, California, United States

GSK Investigational Site

Chino, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

North Hollywood, California, United States

GSK Investigational Site

Orange, California, United States

GSK Investigational Site

Riverside, California, United States

GSK Investigational Site

San Dimas, California, United States

GSK Investigational Site

West Hills, California, United States

GSK Investigational Site

Yuba City, California, United States

GSK Investigational Site

Denver, Colorado, United States

GSK Investigational Site

Daytona Beach, Florida, United States

GSK Investigational Site

Edgewater, Florida, United States

GSK Investigational Site

Fort Lauderdale, Florida, United States

GSK Investigational Site

Jacksonville, Florida, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Ocala, Florida, United States

GSK Investigational Site

Pembroke Pines, Florida, United States

GSK Investigational Site

Port Charlotte, Florida, United States

GSK Investigational Site

Savannah, Georgia, United States

GSK Investigational Site

Evanston, Illinois, United States

GSK Investigational Site

Gurnee, Illinois, United States

GSK Investigational Site

Detroit, Michigan, United States

GSK Investigational Site

Asheville, North Carolina, United States

GSK Investigational Site

Charlotte, North Carolina, United States

GSK Investigational Site

Wilmington, North Carolina, United States

GSK Investigational Site

Winston-Salem, North Carolina, United States

GSK Investigational Site

Columbus, Ohio, United States

GSK Investigational Site

Oklahoma City, Oklahoma, United States

GSK Investigational Site

Portland, Oregon, United States

GSK Investigational Site

Bethlehem, Pennsylvania, United States

GSK Investigational Site

Erie, Pennsylvania, United States

GSK Investigational Site

Uniontown, Pennsylvania, United States

GSK Investigational Site

Arlington, Texas, United States

GSK Investigational Site

Austin, Texas, United States

GSK Investigational Site

Corsicana, Texas, United States

GSK Investigational Site

Greenville, Texas, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

San Antonio, Texas, United States

GSK Investigational Site

Temple, Texas, United States

GSK Investigational Site

Silverdale, Washington, United States

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Brampton, Ontario, Canada

GSK Investigational Site

Greater Sudbury, Ontario, Canada

GSK Investigational Site

London, Ontario, Canada

GSK Investigational Site

Heidelberg, Baden-Wurttemberg, Germany

GSK Investigational Site

Aschaffenburg, Bavaria, Germany

GSK Investigational Site

Lehrte, Lower Saxony, Germany

GSK Investigational Site

Demmin, Mecklenburg-Vorpommern, Germany

GSK Investigational Site

Hamburg, , Germany

Countries

United States; Canada; Germany

References

Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.

Reference Type: DERIVED

PMID: 36005278 (View on PubMed)

Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, Lepore JJ, Cobitz AR. Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia. J Am Soc Nephrol. 2016 Apr;27(4):1234-44. doi: 10.1681/ASN.2014111139. Epub 2015 Oct 22.

Reference Type: DERIVED

PMID: 26494831 (View on PubMed)

Study Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Dataset Specification

View Document

Document Type: Study Protocol

View Document

Document Type: Annotated Case Report Form

View Document

Document Type: Clinical Study Report

View Document

Document Type: Individual Participant Data Set

View Document

Document Type: Informed Consent Form

View Document

Related Links

https://www.clinicalstudydatarequest.com

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Other Identifiers

116581

Identifier Type: -

Identifier Source: org_study_id