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Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD)

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ClinicalTrials.gov Identifier: NCT03400033
Recruitment Status : Active, not recruiting
First Posted : January 17, 2018
Last Update Posted : July 22, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
This Phase 3 study in hemodialysis-dependent subjects with anemia will evaluate the efficacy and safety of daprodustat administered three-times weekly compared to epoetin alfa, the current standard of care. This study includes a 4 week Screening Period, a 52 week Treatment Period and a 4 to 6 week follow-up period. Each subject will remain in the study for up to 62 weeks. Approximately 402 subjects will be randomized to receive either daprodustat three times weekly or epoetin alfa three-times weekly or once weekly, depending on dose level.

Condition or disease Intervention/treatment Phase
Anaemia Drug: Daprodustat tablets Drug: Matching placebo tablets Drug: Epoetin alfa vials Drug: Saline vials or bags Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 402 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Subjects will be randomized to receive either daprodustat or epoetin alfa in a parallel manner. .
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This is a double-blind study, in which the subject, investigator, site staff and the sponsor will remain blinded to each subjects study treatment assignment throughout the course of the study, with the exception of a limited number of unblinded site staff who are necessary to maintain the blind, as well as a limited number of sponsor staff.
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study in Hemodialysis Participants With Anemia of Chronic Kidney Disease to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Recombinant Human Erythropoietin or Its Analogs
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : July 8, 2020
Estimated Study Completion Date : July 8, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Daprodustat
Subjects randomized to this arm will receive daprodustat tablets titrated doses from 2 to 48 milligrams orally three-times weekly along with saline by IV route for the 52 weeks treatment period.
Drug: Daprodustat tablets
Round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.

Drug: Saline vials or bags
0.9% sodium chloride saline vials or bags administered by the IV route.

Active Comparator: Epoetin alfa
Subjects randomized to this arm will receive matching placebo tablets to daprodustat orally three-times weekly and Epoetin alfa by IV route for the 52 weeks treatment period.
Drug: Matching placebo tablets
Matching placebo to daprodustat tablets supplied as round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.

Drug: Epoetin alfa vials
Single-dose, preservative-free vials in unit dose strengths of 2000, 3000, 4000 and 10,000 Units/milliliter administered by the IV route.




Primary Outcome Measures :
  1. Mean change in Hemoglobin (Hgb) between Baseline and over Evaluation period [EP] (Weeks 28 to 52) [ Time Frame: Baseline and up to Week 52 ]
    Blood samples will be collected from subjects for Hgb measurements.


Secondary Outcome Measures :
  1. Mean monthly intravenous (IV) iron dose per subject up to Week 52 [ Time Frame: Up to Week 52 ]
    IV iron use for all subjects will be recorded in the electronic case record form (eCRF) and the average monthly IV iron dose up to Week 52 while on treatment will be calculated.

  2. Number of subjects with adverse events (AEs), serious adverse events (SAEs), adverse event of special interest (AESI) and MACE [ Time Frame: Up to Week 52 ]
    AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is medically significant. Along with AE and SAE the study will also assess AESI and MACE events until follow-up Week 52.

  3. Percentage of time Hgb will be in the analysis range (10 to 11.5 grams/deciliter) over EP (Weeks 28 to 52) [ Time Frame: Weeks 28 to 52 ]
    Subjects will be treated to achieve and maintain Hgb between 10 and 11.5 grams/deciliter. The study treatment may be dose-titrated, if needed, during EP to achieve or maintain Hgb level in the target range.

  4. Time to stopping study treatment due to meeting rescue criteria [ Time Frame: Up to Week 52 ]
    A rescue algorithm is provided to minimize subjects having an inadequate response to the treatment for their anemia for an extended period of time and to enable consistency in the application of rescue therapy across the study. The time to stopping of study treatment due to subjects meeting the rescue criteria will be assessed. The date and time of rescue medication administration as well as the name and dosage regimen of the rescue medication must be recorded.

  5. Number of responders in the Hgb analysis range over EP (Weeks 28 to 52) [ Time Frame: Weeks 28 to 52 ]
    A responder is defined as a subject with mean Hgb within the Hgb analysis range 10 to 11.5 grams/deciliter during the EP. Subjects will be treated to achieve and maintain Hgb between 10 and 11.5 grams/deciliter. The study treatment may be dose-titrated, if needed, during EP to achieve or maintain Hgb level in the target range.

  6. Change from Baseline in SBP, DBP and mean arterial pressure (MAP) at Week 52 and at the end of study treatment [ Time Frame: Baseline and Week 52 ]
    MAP is an average BP in an individual during a single cardiac cycle. Measurements will be taken both pre-dialysis and post-dialysis. Measurements will be taken with the subject is in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period, pre- and post-dialysis. Measurement of SBP, DBP and MAP will be performed before collection of blood samples for laboratory testing, where applicable.

  7. Number of BP exacerbation events per 100 subject years [ Time Frame: Up to Week 52 ]
    The calculation of events per subject-years is the number of incident cases divided by the amount of subjects-time at risk. Number of BP exacerbation events per 100 subject years will be calculated.

  8. Number of subjects with at least one BP exacerbation event during the study [ Time Frame: Up to Week 52 ]
    Number of subjects with at least 1 BP exacerbation event up to Week 52 will be calculated.

  9. Pre-dose trough concentration (Ctau) of daprodustat [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  10. Pre-dose Ctau of metabolites M2 [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  11. Pre-dose Ctau of metabolites M4 [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  12. Pre-dose Ctau of metabolites M3 [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  13. Pre-dose Ctau of metabolites M5 [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  14. Pre-dose Ctau of metabolites M6 [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  15. Pre-dose Ctau of metabolites M13 [ Time Frame: Pre-dose at any one post-Baseline visit between Week 8 and Week 52 ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  16. Maximum observed concentration (Cmax) of daprodustat [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  17. Cmax of metabolites M2 [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours post-dose ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  18. Cmax of metabolites M3 [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours post-dose ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  19. Cmax of metabolites M4 [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours post-dose ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  20. Cmax of metabolites M5 [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours post-dose ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  21. Cmax of metabolites M6 [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours post-dose ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  22. Cmax of metabolites M13 [ Time Frame: Pre-dose and 0.5, 1, 2, 3 hours post-dose ]
    Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one post-Baseline visit between Week 8 and Week 52.

  23. Change from Baseline in Patient Global Impression of Severity (PGI-S) score [ Time Frame: Baseline and up to Week 52 ]
    Change from Baseline in global symptom severity will be assessed. Symptom severity will be assessed using the PGI-S. The PGI-S is a 1-item questionnaire designed to assess subjects impression of disease severity of their anemia of CKD.

  24. Absolute values over time for composite of hematology parameters as a measure of safety [ Time Frame: Up to Week 52 ]
    The following hematology parameters will be measured: Hemoglobin, Hematocrit, RBC count, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), Red cell distribution width (RDW), Reticulocyte count, Platelet count, white blood cell (WBC) count, Total neutrophils, Eosinophils, Monocytes, Basophils, and Lymphocytes

  25. Changes from baseline over time in composite of hematology parameters as a measure of safety [ Time Frame: Up to Week 52 ]
    The following hematology parameters will be measured: Hemoglobin, Hematocrit, RBC count, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), Red cell distribution width (RDW), Reticulocyte count, Platelet count, white blood cell (WBC) count, Total neutrophils, Eosinophils, Monocytes, Basophils, and Lymphocytes

  26. Absolute values over time for composite of chemistry parameters as a measure of safety [ Time Frame: Up to Week 52 ]
    The following chemistry parameters will be measured: Potassium, Albumin, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Calcium, Phosphate, Total and direct/indirect bilirubin, and urea (serum).

  27. Changes from baseline over time in composite of chemistry parameters as a measure of safety [ Time Frame: Up to Week 52 ]
    The following chemistry parameters will be measured: Potassium, Albumin, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Calcium, Phosphate, Total and direct/indirect bilirubin, and urea (serum).

  28. Absolute values of systolic and diastolic blood pressure as a measure of safety [ Time Frame: Up to Week 52 ]
    Measurements will be taken both pre-dialysis and post-dialysis. Measurements will be taken with the subject is in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period, pre and post-dialysis. Measurement of SBP and DBP will be performed before collection of blood samples for laboratory testing, where applicable.

  29. Change from Baseline in systolic and diastolic blood pressure as a measure of safety [ Time Frame: Up to Week 52 ]
    Measurements will be taken both pre-dialysis and post-dialysis. Measurements will be taken with the subject is in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period, pre and post-dialysis. Measurement of SBP and DBP will be performed before collection of blood samples for laboratory testing, where applicable.

  30. Absolute values for heart rate as a measure of safety [ Time Frame: Up to Week 52 ]
    Measurements will be taken both pre-dialysis and post-dialysis. Measurements will be taken with the subject is in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period, pre and post-dialysis. Measurement of heart rate will be performed before collection of blood samples for laboratory testing, where applicable.

  31. Change from Baseline in Heart rate as a measure of safety [ Time Frame: Up to Week 52 ]
    Measurements will be taken both pre-dialysis and post-dialysis. Measurements will be taken with the subject is in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period, pre and post-dialysis. Measurement of heart rate will be performed before collection of blood samples for laboratory testing, where applicable.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Subject must be 18 to 99 years of age inclusive, at the time of signing the informed consent.
  • Use of any approved rhEPO or analog for at least 8 weeks prior to the screening visit and continuing during the screening period until randomization (Day 1).
  • Hgb concentration (measured by HemoCue) within the following range: Week -4: Hgb 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). If Hgb is 11.6 to 11.9 grams/deciliter (7.2 to 7.4 millimoles/liter), up to two retests are allowed; the retest value must be between 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). Day 1: Hgb 8 to 11 grams/deciliter (5 to 6.8 millimoles/liter) and receiving at least the minimum rhEPO or analog dose 3. Hgb>11 to 11.5 grams/deciliter (6.8 to 7.1 millimoles/liter) and receiving greater than the minimum rhEPO or analog dose 3.
  • On hemodialysis (including hemofiltration or hemodiafiltration) >90 days prior to screening and continuing during the screening period.
  • On hemodialysis (in-center) >=3 times per week.
  • 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 A WOCBP who agrees to follow the contraceptive guidance from at least 28 days prior to first dose of study treatment and for at least 28 days after the last dose of study treatment.
  • Capable of giving signed informed consent.
  • In France, a subject will be eligible for inclusion in this study if he or she is either affiliated to or beneficiary of a social security category.

Exclusion Criteria:

  • Planned living-related or living-unrelated kidney transplant within 52 weeks after randomization (Day 1).
  • Ferritin: <=100 nanograms/milliliter (<=100 micrograms/liter), at screening.
  • Transferrin saturation (TSAT): <=20 percent, at screening. If TSAT is 18 to 20 percent, then a retest using a new blood sample can be obtained within 7 days of the final laboratory report; the final retest value must be >20 percent to confirm eligibility.
  • Aplasias: History of bone marrow aplasia or pure red cell aplasia.
  • Conditions, other than anemia of CKD, which can affect erythropoiesis.
  • Myocardial infarction (MI) or acute coronary syndrome within 8 weeks prior to screening through to randomization (Day 1).
  • Stroke or transient ischemic attack within 8 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 as determined by the investigator that would contraindicate the use of rhEPO.
  • Bazett's correction of QTc interval (QTcB): at Day 1: QTcB >500 milliseconds, or QTcB >530 milliseconds in subjects with bundle branch block. There is no QTc (corrected QT) exclusion for subjects with a predominantly ventricular paced rhythm.
  • Liver Disease: presence of any one of the following liver-related laboratory values or conditions, at screening, is exclusionary: ALT >2x upper limit of normal (ULN); Bilirubin >1.5x ULN; or 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.
  • Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR clinically significant gastro intestinal bleeding <= 8 weeks prior to screening through to randomization (Day 1).
  • History of malignancy within 2 years prior to screening through to randomization (Day 1), currently receiving treatment for cancer, or complex kidney cyst (e.g., Bosniak Category IIF, III or IV) >3 centimeters.
  • Use of a strong inhibitor of Cytochrome P4502C8 [CYP2C8] (e.g. gemfibrozil) or a strong inducer of CYP2C8 (e.g. rifampin/rifampicin).
  • History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (daprodustat) or epoetin alfa.
  • 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 treatment duration of >30 days.
  • 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 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): NCT03400033


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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: NCT03400033     History of Changes
Other Study ID Numbers: 204837
2017-004372-56 ( EudraCT Number )
First Posted: January 17, 2018    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 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:
CKD, EPO, rhEPO, Hemodialysis dependent, Daprodustat

Additional relevant MeSH terms:
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Anemia
Kidney Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Hematologic Diseases
Urologic Diseases
Epoetin Alfa
Glycine
Prolyl-Hydroxylase Inhibitors
Hematinics
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Enzyme Inhibitors