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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 : November 14, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this multi-center study in non-dialysis participants 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: Participants 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 participant, 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
Participants 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
Participants 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. Percentage of participants with Hgb increase of >=1.0 grams per deciliter (g/dL) from Baseline [ Time Frame: Baseline and up to Week 28 ]
    Percentage (%) of participants 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. Percentage of Hgb responders [ Time Frame: Baseline and up to Week 28 ]
    Responders will be defined as percentage of participants whose mean Hgb is within target range.

  4. Percentage time Hgb in range [ Time Frame: Up to Week 28 ]
    Percentage time of Hgb within the target range will be analyzed.

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

  6. Time to rescue [ Time Frame: Up to Week 28 ]
    Time to rescue is defined as time to 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 ]
    Mean change from Baseline to week 28 by domain and overall symptom score on the CKD-AQ symptom questionnaire.

  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 the severity and change in symptoms by PGI-S score.

  9. Mean change from Baseline in SF-36 questionnaire vitality domain score [ Time Frame: Baseline and up to Week 28 ]
    Mean Change in individual items of the SF-36 vitality domain score between Baseline and Week 28 will be analyzed.

  10. Mean change from Baseline in SF-36 questionnaire physical function domain score [ Time Frame: Baseline and up to Week 28 ]
    Mean Change in SF-36 physical function domain score between Baseline and Week 28 will be analyzed.

  11. Percentage of participants currently employed on the work productivity and activity impairment, anemia symptoms, clinical practice version (WPAI-ANS-CPV) scale [ Time Frame: Up to Week 28 ]
    Percentage of participants currently employed on WPAI-ANS-CPV; questionnaire will be analyzed.

  12. Change from Baseline in percent mean hours work time missed on the WPAI-ANS [ Time Frame: Baseline and up to Week 28 ]
    Change from Baseline in percent mean hours work time missed using WPAI-ANS-CPV questionnaire will be analyzed.

  13. CPV change from Baseline in percent impaired on the WPAI-ANS-CPV questionnaire [ Time Frame: Baseline and up to Week 28 ]
    CPV change from Baseline in percent impaired on the WPAI-ANS-CPV questionnaire will be analyzed.

  14. Change from Baseline in overall percent work impairment on the WPAI-ANS-CPV questionnaire [ Time Frame: Baseline and up to Week 28 ]
    Change from Baseline in overall percent work impairment using the WPAI-ANS-CPV questionnaire will be analyzed.

  15. Change from Baseline in percent activity impairment on the WPAI-ANS-CPV questionnaire [ Time Frame: Baseline and at Week 28 ]
    Change from Baseline in percent activity impairment using WPAI-ANS-CPV will be analyzed.

  16. Change from Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) score [ Time Frame: Baseline and up to Week 28 ]
    Change from Baseline to Week 28 in health status by EQ-5D-5L score.

  17. Change from Baseline EuroQol Visual Analogue Scale (EQ-VAS) score [ Time Frame: Baseline and up to Week 28 ]
    Change from Baseline to Week 28 in EQ-VAS score.

  18. Change from Baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) at Week 28 [ Time Frame: Baseline and at Week 28 ]
    Change from Baseline in SBP, DBP and MAP at Week 28 will be analyzed.

  19. Percentage of participants with at least one BP exacerbation [ Time Frame: Up to Week 28 ]
    Percentage of participants with at least one BP exacerbation during the study will be analyzed.


Other Outcome Measures:
  1. 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).



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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.
  • Participants 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).
  • Participants 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, participant may be on stable maintenance oral iron supplementation. There should be <50% change in overall dose and no change in type of iron prescribed in the 4 weeks prior to Day 1 randomization visit.
  • Male and female participants are eligible. A female participant 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:

  • Participants 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).
  • Participants 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 other investigational agent or 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 participants with bundle branch block. There is no corrected QT interval (QTc) exclusion for participants 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 participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
  • Current uncontrolled hypertension as determined by the investigator.

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

Publications:
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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: November 14, 2019
Last Verified: November 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