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Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Non-Dialysis (ASCEND-ND)

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ClinicalTrials.gov Identifier: NCT02876835
Recruitment Status : Recruiting
First Posted : August 24, 2016
Last Update Posted : August 15, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this multi-center event-driven study in non-dialysis (ND) participants with anemia associated with chronic kidney disease (CKD) is to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa.

Condition or disease Intervention/treatment Phase
Anaemia Drug: Daprodustat Drug: Darbepoetin alfa Drug: Placebo Drug: Iron Therapy Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 4500 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Non-dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Darbepoetin Alfa
Actual Study Start Date : September 27, 2016
Estimated Primary Completion Date : August 17, 2020
Estimated Study Completion Date : August 17, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Daprodustat
Participants will receive oral daprodustat once daily.
Drug: Daprodustat
The initial dose or oral daprodustat for ESA naïve subjects is based on Hgb and for ESA users is based on prior ESA dose. The dose is adjusted thereafter in order to achieve the target range.

Drug: Placebo
Oral placebo tablets will be taken from Week -4 up to randomization (Day 1).

Drug: Iron Therapy
Participants will receive supplemental iron therapy if ferritin is <=100 ng/mL or TSAT is <=20%. The investigator will choose the route of administration and dose of iron.

Active Comparator: Darbepoetin alfa
Participants will be administered darbepoetin alfa subcutaneously (SC).
Drug: Darbepoetin alfa
The initial dose of darbepoetin alfa to be administered for SC injection for ESA naïve subjects is based in Hgb and weight, and for ESA users is based on converting the prior ESA dose to the nearest available study darbepoetin alfa dose. The dose is adjusted thereafter in order to achieve the target range. IV darbepoetin alfa can be considered for participants transitioning to hemodialysis.

Drug: Placebo
Oral placebo tablets will be taken from Week -4 up to randomization (Day 1).

Drug: Iron Therapy
Participants will receive supplemental iron therapy if ferritin is <=100 ng/mL or TSAT is <=20%. The investigator will choose the route of administration and dose of iron.




Primary Outcome Measures :
  1. Time to the first occurrence of adjudicated major adverse cardiovascular event (MACE) (composite of all-cause mortality, non-fatal myocardial infarction (MI) and non-fatal stroke) [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  2. Mean change in hemoglobin (Hgb) between baseline and efficacy period (EP) (mean over Weeks 28-52) [ Time Frame: Baseline, up to and including Week 52 ]

Secondary Outcome Measures :
  1. Time to first occurrence of adjudicated MACE [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  2. Time to first occurrence of adjudicated MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  3. Time to first occurrence of adjudicated MACE or a hospitalization for heart failure (HF) [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  4. Time to progression of CKD [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  5. Time to first occurrence of all-cause mortality, cardiovascular (CV) mortality, fatal or non-fatal MI, fatal or non-fatal stroke [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  6. Time to first occurrence of MACE or hospitalization for HF (recurrent events analysis) [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  7. Time to first occurrence of CV death or non fatal MI [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  8. Time to first occurrence of all-cause hospitalization [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  9. Time to first occurrence of all cause hospital re-admission within 30 days [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  10. Time to first occurrence of MACE or hospitalization for HF or thromboembolic events [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  11. Time to first occurrence of hospitalization for HF [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  12. Time to first occurrence of thromboembolic events [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  13. Time to first occurrence of individual components of CKD progression [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  14. Hgb change from baseline to Week 52 [ Time Frame: Baseline, up to and including Week 52 ]
  15. Percentage of responders, defined as mean Hgb within the Hgb analysis range [ Time Frame: Up to and including Week 52 ]
  16. Number of responders, defined as mean Hgb within the Hgb analysis range [ Time Frame: Up to and including Week 52 ]
  17. Percentage time for which Hgb is in analysis range during the EP (Week 28 to 52) and during the maintenance period (MP; Week 28 to end of trial) [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  18. Change from baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52 and at end of treatment [ Time Frame: Baseline and up to 4.1 years) ]
  19. Number of blood pressure (BP) exacerbation events per 100 patient years [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  20. Percentage of participants with least one BP exacerbation event during study [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  21. Number of participants with least one BP exacerbation event during study [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  22. Time to stopping randomized treatment due to meeting rescue criteria [ Time Frame: Randomization (Day 1) to end of study (event-driven, up to 4.1 years) ]
  23. Mean change in SF-36 Health Related Quality of Life (HRQOL) scores between Baseline and Weeks 8, 12, 28, 52, of particular interest are the changes from baseline in the vitality and physical functioning domains at Weeks 28 and 52 [ Time Frame: Baseline, up to and including Week 52 ]
  24. Change from Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) score at Week 52 [ Time Frame: Baseline, up to and including Week 52 ]
  25. Change from Baseline in EQ-5D-5L visual analog scale (VAS) at Week 52 [ Time Frame: Baseline, up to and including Week 52 ]
  26. Change from Baseline by domain and overall symptom score on the CKD-Anemia Questionnaire (AQ) at Weeks 8, 12, 28, 52 [ Time Frame: Baseline, up to and including Week 52 ]
  27. Change from Baseline in Patient Global Impression of Severity Scale (PGI-S) at Week 8, 12, 28 and 52 [ Time Frame: Baseline, up to and including Week 52 ]


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age: 18 to 99 years of age (inclusive)
  • CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
  • Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomization.
  • For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL.
  • >=80% and <=120% compliance with placebo during run-in period.
  • Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions.

Exclusion Criteria:

  • Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
  • Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).
  • Ferritin: <=100 nanograms (ng)/milliliter (mL) (<=100 micrograms/liter [L]) at screening.
  • Transferrin saturation (TSAT) (screening only): <=20%.
  • Aplasias: History of bone marrow aplasia or pure red cell aplasia.
  • Other causes of anemia: untreated pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
  • Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant GI bleeding <=4 weeks prior to screening through to randomization (Day 1).
  • MI or acute coronary syndrome: <=4 weeks prior to screening through to randomization (Day 1).
  • Stroke or transient ischemic attack: <=4 weeks prior to screening through to randomization (Day 1).
  • Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system.
  • Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator that would contraindicate the use of recombinant human erythropoietin (rhEPO).
  • Bazett's corrected QT interval (QTcB) (Day 1): QTcB >500 millisecond (msec), or QTcB >530 msec in subjects with bundle branch block. There is no Q-T Interval Corrected for Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm.
  • Alanine transaminase (ALT): >2x upper limit of normal (ULN) at screening.
  • Bilirubin: >1.5xULN at screening.
  • Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
  • Malignancy: 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 (example [e.g.] Bosniak Category II F, III or IV) > 3 centimeter (cm); with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated >=4 weeks prior to screening.
  • Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or darbepoetin alfa.
  • Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
  • Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer).
  • Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of >30 days.
  • Females only: Subject is pregnant [as confirmed by a positive urine human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options.
  • Other Conditions: 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 (e.g., intolerance to darbepoetin alfa) 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): NCT02876835


Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

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

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02876835     History of Changes
Other Study ID Numbers: 200808
First Posted: August 24, 2016    Key Record Dates
Last Update Posted: August 15, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
hemoglobin
anemia
non-dialysis
GSK1278863
erythropoiesis stimulating agents
daprodustat
chronic kidney disease

Additional relevant MeSH terms:
Anemia
Kidney Diseases
Renal Insufficiency, Chronic
Hematologic Diseases
Urologic Diseases
Renal Insufficiency
Darbepoetin alfa
Prolyl-Hydroxylase Inhibitors
Hematinics
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action