Evaluation of Dose Response Relationship, Safety and Efficacy of GSK1278863 in Hemodialysis-dependent Subjects With Chronic Kidney Disease Associated Anemia

NCT01977482 | Completed Phase 2 Results DMC

• 1 other identifier: 113633
• Study Type: interventional
• Target: 216
• Locations: 16 countries
• Sites: 107

Brief Summary

This study is intended to evaluate the dose-response relationship of GSK1278863 over the first 4 weeks of treatment and evaluate the safety and efficacy of GSK1278863 over 24 weeks to maintain hemoglobin (Hgb) level in hemodialysis-dependent (HDD) subjects with anemia associated with chronic kidney disease (CKD) who are switched from a stable dose of recombinant human erythropoietin (rhEPO). The data generated will enable selection of the starting dose(s) and optimize dose adjustment regimen(s) for Phase 3 clinical trials.

Conditions

Anaemia

Keywords

hemoglobin; recombinant human erythropoietin; Chronic kidney disease; hemodialysis; pharmacokinetics; erythropoiesis stimulating agents; Anemia; GSK1278863

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Hemoglobin (Hgb) at Week 4

  Baseline Hgb value was the average of three Hgb values taken during screening period at Week (W) -4, W-2 and Day 1. Change from Baseline in Hgb was calculated as W4 value minus the Baseline value. To model the dose-response relationship a four-parameter Emax model was used. The dose response dataset was based on all non-missing data collected up to W4. Participants (par.) who had a Week 2 Hgb measurement, but a missing Week 4 Hgb measurement were included with a change from Baseline at Week 4 value imputed as twice the change from Baseline at Week 2. E0 is the expected Hgb change from Baseline for a par. receiving placebo and experiencing the average Hgb Baseline observed in the study. Emax is the expected Hgb change from Baseline for a par. receiving the highest dose above which no further increase in response can be achieved. ED50 is the dose that attains the intermediate response. Gamma is the slope parameter. Alpha is the coefficient of the model covariate for centred Baseline.

  Baseline (Week -4, Week-2 and Day 1) and Week 4

Secondary Outcomes (17)

• Hgb Concentration at Week 24

  Week 24

• Percentage of Time Within, Below, and Above Hgb Target Range Between Weeks 20 and 24

  Week 20 to Week 24

• Number of Participants With Hgb in the Target Range at Week 24

  Week 24

• Number of Participants Reaching Pre-defined Hgb Stopping Criteria

  Up to 24 weeks

• Maximum Observed Change From Baseline in Erythropoietin (EPO)

  Baseline (Day 1) to Week 28

Study Arms (6)

GSK1278863 4 mg

EXPERIMENTAL

Subjects will take GSK1278863 4 mg blinded once daily (OD) orally for 4 weeks with a glass of water. From Week 4, study medication will continue to be administered OD and the dose will be adjusted based on Hgb levels dose every 4 weeks till Week 24.

Drug: GSK1278863

GSK1278863 6 mg

EXPERIMENTAL

Subjects will take GSK1278863 6 mg blinded OD orally for 4 weeks with a glass of water. From Week 4, study medication will continue to be administered OD and the dose will be adjusted based on Hgb levels dose every 4 weeks till Week 24.

Drug: GSK1278863

GSK1278863 8 mg

EXPERIMENTAL

Subjects will take GSK1278863 8 mg blinded OD orally for 4 weeks with a glass of water. From Week 4, study medication will continue to be administered OD and the dose will be adjusted based on Hgb levels dose every 4 weeks till Week 24.

Drug: GSK1278863

GSK1278863 10 mg

EXPERIMENTAL

Subjects will take GSK1278863 10 mg blinded OD orally for 4 weeks with a glass of water. From Week 4, study medication will continue to be administered OD and the dose will be adjusted based on Hgb levels dose every 4 weeks till Week 24.

Drug: GSK1278863

GSK1278863 12 mg

EXPERIMENTAL

Subjects will take GSK1278863 12 mg blinded OD orally for 4 weeks with a glass of water. From Week 4, study medication will continue to be administered OD and the dose will be adjusted based on Hgb levels dose every 4 weeks till Week 24.

Drug: GSK1278863

Control

ACTIVE COMPARATOR

Subjects will take GSK1278863 matching placebo blinded OD orally for 4 weeks with a glass of water. From Week 4, rhEPO will be administered and the dose will be adjusted based on Hgb levels dose every 4 weeks till Week 24.

Drug: Placebo; Drug: rhEPO

Interventions

GSK1278863 DRUG

Film coated tablets containing 1 mg, 2 mg, 5 mg, or 25 mg of GSK1278863

GSK1278863 10 mg; GSK1278863 12 mg; GSK1278863 4 mg; GSK1278863 6 mg; GSK1278863 8 mg

Placebo DRUG

Matching placebo tablet for GSK1278863

Control

rhEPO DRUG

rhEPO will be procured from local market

Control

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• General criteria
• Age: \>=18 years of age. (Week -4 verification only)
• Gender: Female and male subjects. (Week -4 verification only) 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 amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) 23.0-116.3 International units per liter (IU/L) and estradiol \<=10 picomole per liter (pmol/L) is confirmatory\]. 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 enrolment. For most forms of HRT, at least 2 weeks 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;
• CKD-related criteria
• Dialysis frequency: On hemodialysis (HD) three to five times weekly for at least 4 weeks prior to Week -4 Screening through Week 4. NOTE: Combination methods including hemofiltration (HF) or ultrafiltration (UF) with HD are allowed. However, the type of dialysis (HD, hemodiafiltration (HDF) or UF) should not change during the study.
• Dialysis adequacy: A 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 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%. NOTE: Only needs confirming at Week -4.
• Hemoglobin: Baseline Hgb of 9.0-11.5 g/dL (may rescreen in a minimum of 2 weeks).
• Stable rhEPO dose: Using the same rhEPO (epoetins or their biosimilars, or darbepoetin) with total weekly doses varying by no more than 50% during the 4 weeks prior to Week -4. At Day 1 (randomization), confirm that total weekly doses varied by no more than 50% during the screening period.
• Iron replacement therapy: Subjects may be on stable maintenance oral or IV (\<=100 mg/week) iron supplementation. If subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to Week -4, during the screening phase, and through the first 4 weeks after Randomization.

You may not qualify if:

• CKD-related criteria
• Dialysis modality: Planned change from HD to peritoneal dialysis within the study time period.
• Renal transplant: Pre-emptive or scheduled renal transplant.
• High rhEPO dose: An epoetin dose of \>=360 IU/Kg/Week IV or \>=250 IU/kg/week subcutaneous (SC) or darbepoetin dose of \>=1.8 microgram (µg)/Kg/Week IV or SC within the prior 8 weeks through Day 1 (randomization).
• Use of methoxy polyethylene glycol epoetin beta within the prior 8 weeks through Day 1 (randomization).
• Laboratory test-based criteria (Week -4 verification only)
• Vitamin B12: At or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks).
• Folate: \<2.0 nanogram (ng)/mL (\<4.5 nanomole (nmol)/L) (may rescreen in a minimum of 4 weeks).
• Ferritin: \<100 ng/mL (\<100 Micrograms per liter).
• Transferrin saturation (TSAT): Outside of the reference range.
• Cardiovascular disease-related criteria
• Myocardial infarction or acute coronary syndrome: Within the 8 weeks prior to Screening through Day 1 (randomization).
• Stroke or transient ischemic attack: Within the 8 weeks prior to Week -4 Screening through Day 1 (randomization).
• Heart failure: Class III/IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system diagnosed prior to Week -4 Screening through Day 1 (randomization); Symptomatic right heart failure diagnosed prior to Week -4 Screening through Day 1 (randomization).
• Hypertension: Defined using pre-dialysis vitals (Week -4, Day 1) of diastolic blood pressure (DBP) \>100 millimeters of mercury (mmHg) or systolic blood pressure (SBP) \>170 mmHg.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (107)

GSK Investigational Site

Azusa, California, 91702, United States

Location

GSK Investigational Site

Los Angeles, California, 90022, United States

Location

GSK Investigational Site

Los Angeles, California, 90025, United States

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GSK Investigational Site

San Dimas, California, 91773, United States

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GSK Investigational Site

West Hills, California, 91307, United States

Location

GSK Investigational Site

Lauderdale Lakes, Florida, 33313, United States

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GSK Investigational Site

Pembroke Pines, Florida, 33028, United States

Location

GSK Investigational Site

Macon, Georgia, 31217, United States

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GSK Investigational Site

Evergreen Park, Illinois, 60805, United States

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GSK Investigational Site

Bethesda, Maryland, 20814, United States

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GSK Investigational Site

Farmington, Missouri, 63640, United States

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GSK Investigational Site

Amherst, New York, 14226, United States

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GSK Investigational Site

The Bronx, New York, 10461, United States

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GSK Investigational Site

Charlotte, North Carolina, United States

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GSK Investigational Site

Knoxville, Tennessee, 37923, United States

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GSK Investigational Site

San Antonio, Texas, 78229, United States

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GSK Investigational Site

Temple, Texas, 76502, United States

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GSK Investigational Site

Liverpool, New South Wales, 2170, Australia

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GSK Investigational Site

Westmead, New South Wales, 2145, Australia

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GSK Investigational Site

Woolloongabba, Queensland, 4102, Australia

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GSK Investigational Site

Adelaide, South Australia, 5000, Australia

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GSK Investigational Site

Nedlands, Western Australia, 6009, Australia

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GSK Investigational Site

Calgary, Alberta, T2R 0X7, Canada

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GSK Investigational Site

Edmonton, Alberta, T6G 2B7, Canada

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GSK Investigational Site

Greater Sudbury, Ontario, P3E 5J1, Canada

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GSK Investigational Site

Kitchener, Ontario, N2G 1G3, Canada

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GSK Investigational Site

London, Ontario, N6A 5A5, Canada

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GSK Investigational Site

Montreal, Quebec, H1T 2M4, Canada

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GSK Investigational Site

Liberec, 460 63, Czechia

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GSK Investigational Site

Louny, 440 01, Czechia

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GSK Investigational Site

Most, 434 64, Czechia

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GSK Investigational Site

Prague, 100 34, Czechia

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GSK Investigational Site

Prague, 128 08, Czechia

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GSK Investigational Site

Prague, 142 00, Czechia

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GSK Investigational Site

Sokolov, 356 01, Czechia

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GSK Investigational Site

Odense C, 5000, Denmark

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GSK Investigational Site

Roskilde, DK-4000, Denmark

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GSK Investigational Site

Amiens, 80054, France

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GSK Investigational Site

Bordeaux, 33000, France

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GSK Investigational Site

Caen, 14033, France

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GSK Investigational Site

Paris, 75743, France

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GSK Investigational Site

Mannheim, Baden-Wurttemberg, 68167, Germany

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GSK Investigational Site

Munich, Bavaria, 81675, Germany

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GSK Investigational Site

Demmin, Mecklenburg-Vorpommern, 17109, Germany

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GSK Investigational Site

Düsseldorf, North Rhine-Westphalia, 40210, Germany

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GSK Investigational Site

Leipzig, Saxony, 04129, Germany

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GSK Investigational Site

Berlin, 12053, Germany

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GSK Investigational Site

Hamburg, 22297, Germany

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GSK Investigational Site

Budapest, 1115, Hungary

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GSK Investigational Site

Esztergom, 2500, Hungary

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GSK Investigational Site

Pécs, 7624, Hungary

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GSK Investigational Site

Pécs, 7633, Hungary

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GSK Investigational Site

Aichi, 441-8023, Japan

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GSK Investigational Site

Ehime, 790-0952, Japan

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GSK Investigational Site

Ehime, 790-0962, Japan

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GSK Investigational Site

Fukuoka, 803-0844, Japan

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GSK Investigational Site

Kyoto, 617-0813, Japan

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GSK Investigational Site

Niigata, 940-0053, Japan

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GSK Investigational Site

Wakayama, 640-8335, Japan

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GSK Investigational Site

Yamagata, 990-0834, Japan

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GSK Investigational Site

Oslo, 0027, Norway

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GSK Investigational Site

Oslo, 0405, Norway

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GSK Investigational Site

Stavanger, 4011, Norway

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GSK Investigational Site

Trondheim, 7006, Norway

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GSK Investigational Site

Tønsberg, 3116, Norway

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GSK Investigational Site

Krakow, 31-501, Poland

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GSK Investigational Site

Tarnów, 33-100, Poland

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GSK Investigational Site

Warsaw, 02-507, Poland

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GSK Investigational Site

Zabrze, 41-800, Poland

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GSK Investigational Site

Kaluga, 248007, Russia

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GSK Investigational Site

Krasnodar, 350029, Russia

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GSK Investigational Site

Krasnogorsk, 143400, Russia

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GSK Investigational Site

Moscow, 125101, Russia

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GSK Investigational Site

Mytischi, 141009, Russia

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GSK Investigational Site

Novosibirsk, 630087, Russia

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GSK Investigational Site

Saint Petersburg, 191104, Russia

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GSK Investigational Site

Saint Petersburg, 194354, Russia

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GSK Investigational Site

Yaroslavl, 150062, Russia

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GSK Investigational Site

Anyang-Si Gyeonggi-do, 431-070, South Korea

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GSK Investigational Site

Daegu, 700-721, South Korea

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GSK Investigational Site

Daejeon, 301-721, South Korea

Location

GSK Investigational Site

Gwangju, 501-757, South Korea

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GSK Investigational Site

Incheon, 405-760, South Korea

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GSK Investigational Site

Seoul, 120-752, South Korea

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GSK Investigational Site

Alcalá de Henares, 28805, Spain

Location

GSK Investigational Site

Alicante, 03010, Spain

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GSK Investigational Site

Almería, 04009, Spain

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GSK Investigational Site

Badalona, 08916, Spain

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GSK Investigational Site

Barcelona, 08907, Spain

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GSK Investigational Site

Córdoba, 14004, Spain

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GSK Investigational Site

Granada, 18014, Spain

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GSK Investigational Site

Madrid, 28007, Spain

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GSK Investigational Site

Madrid, 28224, Spain

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GSK Investigational Site

San Sebastián de los Reyes, 28702, Spain

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GSK Investigational Site

Santander, 39008, Spain

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GSK Investigational Site

Santiago de Compostela, 15706, Spain

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GSK Investigational Site

Karlstad, SE-651 85, Sweden

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GSK Investigational Site

Örebro, SE-701 85, Sweden

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GSK Investigational Site

Stockholm, SE-141 86, Sweden

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GSK Investigational Site

Uppsala, SE-751 85, Sweden

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GSK Investigational Site

Chelmsford, CM1 7ET, United Kingdom

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GSK Investigational Site

Dorchester, DT1 2JY, United Kingdom

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GSK Investigational Site

Dundee, DD1 9SY, United Kingdom

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GSK Investigational Site

Hull, HU3 2JZ, United Kingdom

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GSK Investigational Site

London, E1 1BB, United Kingdom

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GSK Investigational Site

Manchester, M13 9WL, United Kingdom

Location

GSK Investigational Site

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 36005278 DERIVED

MeSH Terms

Conditions

Anemia; Renal Insufficiency, Chronic

Interventions

GSK1278863

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2013
• First Posted: November 6, 2013
• Study Start: November 1, 2013
• Primary Completion: February 1, 2015
• Study Completion: February 6, 2015
• Last Updated: June 8, 2018
• Results First Posted: February 14, 2017

Record last verified: 2018-05

Locations

GB (7); DE (7); CZ (7); DK (2); HU (4); NO (5); ES (12); RU (9); AU (5); SE (4); PL (4); CA (6); FR (4); KR (6); US (17); JP (8)