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Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-in Incident Dialysis (ASCEND-ID)

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ClinicalTrials.gov Identifier: NCT03029208
Recruitment Status : Active, not recruiting
First Posted : January 24, 2017
Last Update Posted : November 5, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
The purpose of this multi-center study is to evaluate the efficacy and safety of daprodustat in subjects with anemia associated with CKD.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 52-week Open-label (Sponsor-blind), Randomized, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Efficacy and Safety of Daprodustat Compared to Recombinant Human Erythropoietin in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Initiating Dialysis
Actual Study Start Date : May 11, 2017
Estimated Primary Completion Date : October 8, 2020
Estimated Study Completion Date : October 8, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Daprodustat treated anemic subjects
Subjects will receive oral daprodustat once daily.
Drug: Daprodustat
Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 4, 6, 8, or 10 mg of daprodustat. Doses of 12, 16, and 24 mg of daprodustat will be provided using multiples of these tablet strengths.

Drug: Iron therapy
Iron therapy will be administered if ferritin is <=100 ng/mL and/or TSAT is <=20%.

Active Comparator: Darbepoetin alfa treated anemic subjects
Subjects will receive darbepoetin alfa subcutaneously or intravenously.
Drug: Darbepoetin alfa
Darbepoetin alfa will be supplied as prefilled syringes (PFS) for SC/IV injection available in strengths: 20, 30, 40, 60, 80, 100 and 150 mcg.

Drug: Iron therapy
Iron therapy will be administered if ferritin is <=100 ng/mL and/or TSAT is <=20%.




Primary Outcome Measures :
  1. Mean change from Baseline in hemoglobin (Hgb) during evaluation period (EP) [ Time Frame: Randomization (Day 1) to Week 52 ]
    The Baseline Hgb will be the value obtained on Day 1. The EP is defined as the period from the end of the stabilization period (Week 28) to Week 52.


Secondary Outcome Measures :
  1. Average monthly IV iron dose milligrams (mg) per subject from Baseline to Week 52 [ Time Frame: Randomization (Day 1) to Week 52 ]
    IV iron use for all subjects will be recorded and the average monthly IV iron dose up to week 52 while on treatment will be calculated.

  2. Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52 [ Time Frame: Randomization (Day 1) to Week 52 ]
    SBP and DBP will be measured at each study visit. Change from Baseline will be calculated as post dose value minus Baseline value.

  3. Number of BP exacerbation events per 100 patient years [ Time Frame: Up to Week 58 ]
    SBP and DBP will be measured at each study visit.

  4. Number (%) of subjects with at least one BP exacerbation event during study [ Time Frame: Up to Week 58 ]
    SBP and DBP will be measured at each study visit.

  5. Change from Baseline in Hgb up to Week 52 [ Time Frame: Baseline and up to Week 52 ]
    Change from Baseline will be calculated as post dose value minus Baseline value.

  6. Number (%) of Hgb responders [ Time Frame: Week 28 to Week 52 ]
    Responders will be defined as subjects with mean Hgb within Hgb analysis range during the EP

  7. Percentage time for which Hgb is in analysis range during the EP [ Time Frame: Week 28 to Week 52 ]
    Analysis range is from 10-11.5 g/dL.

  8. Time to rescue [ Time Frame: Up to Week 52 ]
    Rescue is defined as permanently stopping randomized treatment due to meeting rescue criteria.

  9. Change in short form (SF)-36 health-related quality of life (HRQOL) scores [ Time Frame: Baseline and up to Week 52 ]
    Mean change in SF-36 HRQOL score between Baseline and Weeks 8, 12, 28, 52 will be determined.

  10. Change from Baseline in Health Utility EuroQol five dimensions five level (EQ-5D-5L) questionnaire score at Week 52 [ Time Frame: Baseline and Week 52 ]
    Change from Baseline in EQ-5D-5L score at Week 52.

  11. Change from Baseline in EQ visual analogue scale (VAS) at Week 52 [ Time Frame: Baseline and Week 52 ]
    Change from Baseline in EQVAS at Week 52.

  12. Change from Baseline in the CKD- Anemia Symptoms Questionnaire (AQ) [ Time Frame: Baseline and Week 52 ]
    Change from Baseline to Week 52 by domain and overall symptom score.

  13. Change from Baseline in patient global impression of severity (PGI-S) [ Time Frame: Baseline and up to Week 52 ]
    Change from Baseline to Week 52 in symptom severity score.

  14. Summary of pharmacokinetic parameters of plasma daprodustat and three major metabolites in dialysis subjects [ Time Frame: Predose, 0.5, 1, 2, and 3 hours post dose at Week 4, 8 or 12 ]
    Pharmacokinetic parameters that is, pre-dose trough (Ctau) and maximum observed concentration (Cmax) of daprodustat and three major metabolites (M2, M3 and M13).



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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:

  • 18 to 99 years of age inclusive.
  • Planning to start chronic dialysis within the next 6 weeks (from the date of the screening visit) OR have started and received dialysis (as specified below) for end-stage renal disease for a maximum of <=90 days immediately prior to randomization and is not expected to stop dialysis during the duration of the trial: HD >=2 times per week or PD >=4 times per week including incremental schedule; subjects on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) are eligible.
  • Hemoglobin concentration as measured by HemoCue (range inclusive): 8 to 10.5 g/dL (5-6.5 millimoles per liter [mmol/L]) at screening and 8-11.0 g/dL (5 to 6.8 mmol/L) at randomization.
  • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

  • Planned living-related or living-unrelated kidney transplant during the study.
  • Ferritin: <=100 nanograms per milliliter (ng/mL) (<=100 micrograms per liter [mcg/L]) at screening or after IV iron supplementation.
  • Transferrin saturation (TSAT): <=20% at screening or after IV iron supplementation.
  • Vitamin B12 (cobalamin): Below the lower limit of the reference range at screening or after vitamin B12 supplementation.
  • Folate: <2.0 ng/mL (<4.5 nanomoles per liter [nmol/L]) at screening.
  • Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA).
  • 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 <=10 weeks prior to screening through to randomization (Day 1).
  • Use of any Erythropoiesis-stimulating agent (ESA) treatment within 8 weeks prior to screening except for limited use as part of dialysis initiation. Note : Limited use is defined as no more than 6 weeks of short acting ESA (rhEPO or biosimilars; maximum of 20000 unit total) or long acting ESA (darbepoetin alfa [maximum of 100 mcg total] or methoxy polyethylene glycol-epoetin beta [maximum of 125 mcg total]) received before or after starting dialysis.
  • Myocardial infarction or acute coronary syndrome: <=10 weeks prior to screening through to randomization (Day 1).
  • Stroke or transient ischemic attack: <=10 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.
  • Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of rhEPO.
  • QT correction using Bazett's (QTcB) (Day 1): QTcB >500 milliseconds (msec), or QTcB >530 msec in subjects with bundle branch block. There is no QTc exclusion for subjects with a predominantly ventricular paced rhythm.
  • Liver disease (any one of the following): 1. Alanine transaminase (ALT) >2 times upper limit of normal (ULN) (screening only). 2. Bilirubin >1.5 times ULN (screening only) (NOTE: Isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 3. 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. NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic hepatitis B or C, or Gilbert's syndrome) are acceptable if subject otherwise meets entry criteria.
  • 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 (i.e. Bosniak Category II F, III or IV) >3 centimeter (cm). The only exception is localized squamous cell or basal cell carcinoma of the skin that has been definitively treated >=10 weeks prior to screening.
  • History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product or to darbepoetin alfa.
  • Use of strong Cytochrome P4502C8 (CYP2C8) inhibitors (example gemfibrozil) or strong CYP2C8 inducers (example rifampin/rifampicin).
  • 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).
  • Any prior treatment with daprodustat for treatment duration of >30 days.
  • Females only: Subject is pregnant [as confirmed by a positive serum human chorionic gonadotropin (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 in the List of Highly Effective Methods for Avoiding Pregnancy.
  • 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 (example intolerance to rhEPO) 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): NCT03029208


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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: NCT03029208     History of Changes
Other Study ID Numbers: 201410
2016-000507-86 ( EudraCT Number )
First Posted: January 24, 2017    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: November 2019

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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:
Daprodustat, recombinant human erythropoietin, darbepoetin, anemia, chronic kidney disease, dialysis, ESRD
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Anemia
Hematologic Diseases
Urologic Diseases
Renal Insufficiency
Darbepoetin alfa
Glycine
Hematinics
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs