Study in dialysis subjects with anemia of chronic kidney disease to assess safety and efficacy of daprodustat compared to erythropoietin

• Register: EUCTR
• Last refreshed on: 7 December 2020
• Main ID: EUCTR2016-000541-31-HU
• Date of registration: 18/10/2016
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: Study in dialysis subjects with anemia of chronic kidney disease to assess safety and efficacy of daprodustat compared to erythropoietin
• Scientific title: A phase 3 randomized, open-label (sponsor-blind), activecontrolled, parallel-group, multi-center, event driven study in dialysis subjects with anemia associated with chronic kidney disease to evaluate the safety and efficacy of daprodustat compared to recombinant human erythropoietin, following a switch from erythropoietin-stimulating agents. - Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Dialysis (ASCEND-D)
• Date of first enrolment: 02/12/2016
• Target sample size: 3000
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000541-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, India, Italy, Korea, Democratic People's Republic of, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

• Name: Clinical Trials Helpdesk
• Affiliation: GlaxoSmithKline Research & Development Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
A subject will be eligible for inclusion in this study only if all of the following criteria apply at screening (Week -8) and randomization (Day 1) unless otherwise specified.
1. Age (confirm at screening only): 18 to 99 years of age (inclusive).
2. ESAs: Use of any approved ESA for at least the 6 weeks prior to screening and between screening and randomization.
3. Hgb concentration measured by HemoCue (range is specified in protocol)
4. Dialysis: On dialysis > 90 days prior to screening and continuing on the same mode of dialysis from screening (Week -8) through to randomization (Day 1).
5. Frequency of Dialysis:
- HD (in-center): =2 times/week
- PD: =5 times/week
- Home HD: (=2times/week)
6. Compliance with placebo [randomization (Day 1) only]: =80% and =120% compliance with placebo during run-in period (NOTE: this is in addition to ESA treatment).
7. Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 900

Exclusion criteria:
A subject will not be eligible for inclusion in this study if any of the following criteria apply at screening (Week -8) or randomization (Day 1), unless otherwise specified.
CKD related criteria
1. Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).

Anemia related criteria
2. Ferritin (screening only): =100 ng/mL (=100 ug/L).
3. Transferrin saturation (TSAT) (screening only): =20%. If TSAT is 18-20%, 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% to confirm eligibility.
4. Aplasias: History of bone marrow aplasia or pure red cell aplasia.
5. Other causes of anemia: Untreated pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
6. 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).

CV disease-related criteria
7. MI or acute coronary syndrome: =4 weeks prior to screening through to randomization (Day 1).
8. Stroke or transient ischemic attack: =4 weeks prior to screening through to randomization (Day 1).
9. Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system.
10. Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator that would contraindicate the use of rhEPO.
11. QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle branch block. There is no QTc exclusion for subjects with a predominantly ventricular paced rhythm.

Other disease-related criteria
12. Liver disease: (any one of the following):
- Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)
- Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.
- Current unstable liver or biliary disease per investigator assessment, generally by the presence of ascites,
encephalopathy, coagulopathy, hypoalbuminaemia, 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.
13. 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 (e.g. Bosniak Category II F, III or IV) > 3cm. Note: The only exception is localized squamous cell or basal cell carcinoma of the skin that has been definitively treated 4 weeks prior to screening.

Concomitant medication and other randomized treatment-related criteria
14. Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (refer to daprodustat IB), or epoetin alfa or darbepoetin alfa (refer to product labeling).
15. Drugs and supplements: Use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
16. Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1).
•Note: at screening, this exclusion applies to use of the investigational agent within 30 days or with

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Anemia associated with chronic kidney disease
MedDRA version: 20.0 Level: PT Classification code 10064848 Term: Chronic kidney disease System Organ Class: 10038359 - Renal and urinary disorders

Therapeutic area: Body processes [G] - Physiological processes [G07]

Intervention(s)

Product Name: Daprodustat
Product Code: GSK1278863
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: daprodustat
CAS Number: 960539-70-2
Current Sponsor code: GSK1278863A (A denotes the free acid)
Other descriptive name: GSK1278863
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1 -
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Daprodustat
Product Code: GSK1278863
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: daprodustat
CAS Number: 960539-70-2
Current Sponsor code: GSK1278863A (A denotes the free acid)
Other descriptive name: GSK1278863
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2 -
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Daprodustat
Product Code: GSK1278863
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: daprodustat
CAS Number: 960539-70-2
Current Sponsor code: GSK1278863A (A denotes the free acid)
Other descriptive name: GSK1278863
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4 -
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Daprodustat
Product Code: GSK1278863
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: daprodustat
CAS Number: 960539-70-2
Current Sponsor code: GSK1278863A (A denotes the free acid)
Other descriptive name: GSK1278863
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 6-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Daprodustat
Product Code: GSK1278863
Pharm

Primary Outcome(s)

Primary end point(s): •Time to first occurrence of adjudicated MACE (composite of all-cause mortality, non-fatal MI and non-fatal stroke)
•Mean change in Hgb between baseline and EP (mean over Weeks 28 to 52)

Secondary Objective: • To compare daprodustat to rhEPO on CV safety endpoints
• To compare daprodustat to rhEPO on the use of intravenous (IV) iron

Main Objective: •To compare daprodustat to recombinant human erthropoetin (rhEPO) for cardiovascular (CV) safety (non-inferiority)
•To compare daprodustat to recombinant human erthropoetin (rhEPO) for hemoglobin (Hgb) efficacy (non-inferiority)

Timepoint(s) of evaluation of this end point: Endpoint 1: evaluated throughout the study until the accumulation of 945 adjudicated first MACE
Endpoint 2: Between week 28 and week 52

Secondary Outcome(s)

Secondary end point(s): Time to first occurrence of adjudicated:
•MACE
•MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism)
•MACE or a hospitalization for heart failure (HF)
•Average monthly IV iron dose (mg)/subject to week 52

Timepoint(s) of evaluation of this end point: - Evaluation of endpoint is dependent upon the accumulation of 945 adjudicated first MACE (i.e., it is event-driven).

Secondary ID(s)

200807

Source(s) of Monetary Support

GlaxoSmithKline Research & Development Ltd

Ethics review

Status: Approved
Approval date: 22/11/2016
Contact: