Study in subjects with anemia of chronic kidney disease to assess safety and efficacy of daprodustat compared to darbepoetin alfa.

Phase 1

• Conditions: Anemia associated with chronic kidney disease; MedDRA version: 20.0Level: PTClassification code 10064848Term: Chronic kidney diseaseSystem Organ Class: 10038359 - Renal and urinary disorders; Therapeutic area: Body processes [G] - Physiological processes [G07]

• Registration Number: EUCTR2016-000542-65-HU
• Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-10-18
• Last Update Posted: 26 April 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 4500

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.CKD stage (confirm at screening only): Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009].
3.ESAs:
•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 (see footnote in protocol) for the 6 weeks prior to screening and continuing between screening and randomization.
4.HemoCue Hgb (range is specified in protocol): Hgb defined by ESA use
5.Compliance with placebo [randomization (Day 1) only]: =80% and =120% compliance with placebo during run-in period (NOTE: for ESA users, this is in addition to ESA treatment).
6.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 2250
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2250

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply at screening (Week -8) and randomization (Day 1), unless otherwise specified.
CKD related criteria
1.Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
2.Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).

Anemia-related criteria
3.Ferritin (screening only): =100 ng/mL (=100 ug/L).
4.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.
5.Aplasias: History of bone marrow aplasia or pure red cell aplasia.
6.Other causes of anemia: Untreated pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
7.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
8.MI or acute coronary syndrome: =4 weeks prior to screening through to randomization (Day 1).
9.Stroke or transient ischemic attack: =4 weeks prior to screening through to randomization (Day 1).
10.Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system.
11.Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator that would contraindicate the use of rhEPO.
12.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
13.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 defined 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.
14.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
15.Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (refer to daprodustat IB) or darbepoetin alfa (refer to product labeling).
16.Drugs and supplements: Use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
17.Other study participation: Use of other investigational agent or device prior to screening through to randomizatio

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: •To compare daprodustat to darbepoetin alfa for cardiovascular (CV) safety (non-inferiority)<br>•To compare daprodustat to darbepoetin alfa for hemoglobin (Hgb) efficacy (non-inferiority);Secondary Objective: • To compare daprodustat to darbepoetin on CV safety endpoints<br>• To compare daprodustat to darbepoetin on the use of intravenous (IV) iron;Primary end point(s): •Time to first occurrence of adjudicated MACE (composite of all-cause mortality, non-fatal MI and non-fatal stroke)<br>•Mean change in Hgb between baseline and EP (mean over Weeks 28 to 52);Timepoint(s) of evaluation of this end point: Endpoint 1: evaluated at the time to first occurrence of adjudicated MACE<br>Endpoint 2: Between week 28 and week 52

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Time to first occurrence of adjudicated:<br>•MACE<br>•MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism)<br>•MACE or a hospitalization for heart failure (HF)<br>;Timepoint(s) of evaluation of this end point: - Time to progression of adjudicated MACE<br>- Time to progression of CKD1 [Progression of CKD defined as: 40% decline in estimated glomerular filtration rate (eGFR) from baseline (confirmed 4-13 weeks later) OR end stage renal disease (ESRD)]