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Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ)

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ClinicalTrials.gov Identifier: NCT03409107
Recruitment Status : Recruiting
First Posted : January 24, 2018
Last Update Posted : August 9, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this multi-center study in non-dialysis subjects with anemia associated with CKD is to evaluate safety, efficacy and quality of life of daprodustat compared to placebo.

Condition or disease Intervention/treatment Phase
Anaemia Drug: Daprodustat (GSK1278863) Drug: Placebo Drug: Iron therapy Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects will be randomized to receive Daprodustat or placebo in a randomized manner.
Masking: Double (Participant, Investigator)
Masking Description: This will be a double-blind study. The subject, investigator, site staff, and study team will be blinded to the assigned study treatment.
Primary Purpose: Treatment
Official Title: A 28-week, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center, Study in Recombinant Human Erythropoietin (rhEPO) naïve Non-dialysis Participants With Anemia Associated With Chronic Kidney Disease to Evaluate the Efficacy, Safety and Effects on Quality of Life of Daprodustat Compared to Placebo
Actual Study Start Date : March 5, 2018
Estimated Primary Completion Date : November 5, 2020
Estimated Study Completion Date : November 5, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Daprodustat receivers
Subjects will receive oral daprodustat once daily
Drug: Daprodustat (GSK1278863)
Daprodustat will be available as 9 millimeter (mm) or 7 mm film-coated tablets. Daprodustat will be administered once daily via oral route and can be taken without regard to food.

Drug: Iron therapy
Iron therapy will be administered if ferritin is <=50 Nano gram per milliliter and/or TSAT is <=15 percent.

Placebo Comparator: Placebo receivers
Subjects will receive oral placebo once daily
Drug: Placebo
Daprodustat matching placebo will be available as 9 mm or 7 mm film coated tablets. Placebo will be administered once daily via oral route and can be taken without regard to food.

Drug: Iron therapy
Iron therapy will be administered if ferritin is <=50 Nano gram per milliliter and/or TSAT is <=15 percent.




Primary Outcome Measures :
  1. Mean change from Baseline in Hgb up to evaluation period (EP) [ Time Frame: Baseline and up to Week 28 ]
    The EP is from Week 24 to Week 28.


Secondary Outcome Measures :
  1. Number of subjects with Hgb increase of >=1.0 grams per deciliter (g/dL) from Baseline [ Time Frame: Baseline and up to Week 28 ]
    Number of subjects having a Hgb increase of >=1.0 g/dL from Baseline to EP.

  2. Mean change from Baseline in short form-36 (SF-36) questionnaire vitality domain score [ Time Frame: Baseline and Week 28 ]
    Mean Change in SF-36 Vitality domain score between Baseline and Week 28.

  3. Incidences and severity of adverse events (AEs) and serious AEs (SAEs) [ Time Frame: Up to Week 32 ]
    Includes AEs of special interest and adjudicated Major adverse cardiovascular event (MACE) (composite of all-cause mortality, non-fatal Myocardial infarction [MI] and non-fatal stroke).

  4. Number of Hgb responders [ Time Frame: Baseline and up to Week 28 ]
    Responders will be defined as subjects whose mean Hgb is within target range.

  5. Mean change from Baseline for additional Hgb parameters [ Time Frame: Baseline and up to Week 28 ]
    Percentage time Hgb in range and mean change in Hgb from Baseline.

  6. Time to rescue [ Time Frame: Up to Week 28 ]
    Rescue is defined as permanently stopping randomized treatment due to meeting rescue criteria.

  7. Mean change from Baseline in CKD - Anemia Questionnaire (CKD-AQ) score [ Time Frame: Up to Week 28 ]
    Change from Baseline to week 28 by domain and overall symptom score.

  8. Change from Baseline in Patient Global Impression of Severity (PGI-S) score [ Time Frame: Baseline and up to Week 28 ]
    Change from Baseline to Week 28 in symptom severity score.

  9. Change from Baseline in work productivity and daily regular activity impairment [ Time Frame: Baseline and up to Week 28 ]
    Change for Baseline to week 28 in mean hours work time missed on the work productivity and activity impairment (WPAI-ANS-CPV) scale.

  10. Change from Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) score [ Time Frame: Baseline and up to Week 28 ]
    The EQ-5D-5L is a self-reported descriptive system of health-related quality of life states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can take one of five responses. The EQ-5D-5L score ranges from 1= no problem to 5= extreme problems. A unique health state is defined by combining score from each of the five dimensions.

  11. Change from Baseline EuroQol Visual Analogue Scale (EQ-VAS) score [ Time Frame: Baseline and up to Week 28 ]
    The EQ-VAS is a part of EQ-5D-5L heath status. The EQ VAS records the self-rated health of a subject on a 20 cm vertical, visual analogue scale. The scale ranges from 0= 'the worst health you can imagine' to 100= 'the best health you can imagine'. This instrument can be used as a quantitative measure of health as judged by the individual.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • >=18 years of age at the time of signing the informed consent.
  • Have CKD, confirmed at screening: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by Estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
  • Subjects with Stable HemoCue Hgb from 8.5 to 10.5 at screening visit (Week -4) and from 8.5 to 10.0 g/dL at randomization (Day 1).
  • Subjects may receive up to one intravenous (IV) iron dose within the 8 weeks prior to screening and NO IV iron use between screening visit and randomization (Day 1).
  • If needed, subject may be on stable maintenance oral iron supplementation. The type of iron and dose must not be changed for the 4 weeks prior to screening (Week -4), through the screening period, and until randomization (Day 1).
  • Male and female subjects are eligible. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 weeks after the last dose of study treatment.
  • Capable of giving signed informed consent.

Exclusion Criteria:

  • Subjects who are on dialysis or clinical evidence of impending need to initiate dialysis within 180 days after randomization (Day 1).
  • Planned living-related or living-unrelated kidney transplant within 28 weeks after randomization (Day 1).
  • Transferrin saturation (TSAT) <15 percent (Screening only).
  • Ferritin <50 nanograms per milliliter (ng/mL) (Screening only).
  • History of rhEPO or rhEPO analogue use within the 8 weeks prior to screening and rhEPO use between screening and randomization (Day 1).
  • History of transfusion within the 8 weeks prior to screening and transfusion between screening and randomization (Day 1).
  • History of bone marrow aplasia or pure red cell aplasia (PRCA).
  • Subjects with Megaloblastic anemia (untreated pernicious anemia and folate deficiency), thalassemia major, sickle cell disease or myelodysplastic syndrome.
  • Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal (GI) bleeding <= 8 weeks prior to screening through to randomization (Day 1).
  • History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
  • Use of strong inhibitor of CYP2C8 (for example, gemfibrozil) or strong inducers of CYP2C8 (for example, rifampin/rifampicin).
  • Ferric citrate use within 4 weeks prior to randomization (Day 1).
  • Use of another investigational agent within 30 days or within five half-lives of the investigational agent (whichever is longer) or currently participating in a study of an investigational device prior to screening through to randomization (Day 1).
  • Any prior treatment with daprodustat for a treatment duration of >30 days.
  • MI or acute coronary syndrome within the 8 weeks prior to screening through to randomization. (Day 1).
  • Stroke or transient ischemic attack within the 8 weeks prior to screening through to randomization. (Day 1).
  • Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.
  • QT interval corrected by Bazett's formula (QTcB) >500 milliseconds (msec) or QTcB >530 msec in subjects with bundle branch block. There is no corrected QT interval (QTc) exclusion for subjects with a predominantly paced rhythm.
  • Alanine transaminase (ALT) >2x upper limit of normal (ULN) at screening (Week -4).
  • Bilirubin >1.5xULN at screening (Week -4).
  • Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
  • History of malignancy within the 2 years prior to screening through to randomization (Day 1), or currently receiving treatment for cancer, or complex kidney cyst (for example, Bosniak Category II F, III or IV) > 3 centimeters (cm).
  • Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03409107


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03409107     History of Changes
Other Study ID Numbers: 205270
2017-002270-39 ( EudraCT Number )
First Posted: January 24, 2018    Key Record Dates
Last Update Posted: August 9, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Non-Dialysis
Anemia
Chronic kidney disease
Recombinant human erythropoietin naïve
Hemoglobin
Daprodustat
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Anemia
Hematologic Diseases
Urologic Diseases
Renal Insufficiency
Glycine
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs