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

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: EUCTR2016-000541-31-FR
• Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-12-16
• Last Update Posted: 5 April 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 3000

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: =2 times/wk
? - PD: Daily PD
? - Home HD: short daily or nocturnal (=3x/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: 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 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%.
4. Aplasias: History of bone marrow aplasia or pure red cell aplasia.
5. Other causes of anemia: 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 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. Prior investigational product exposure: Use of an investigational agent = 30 days or within five half lives of the investigational agent (whichever is longer) prior to screening.
17. Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of > 30 days.

General health-related criteria
18. Females ONLY: Subject is pregnant [as confirmed by a positive serum human chorionic gonadot

Study & Design

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

Primary Outcome Measures

Name	Time	Method
Timepoint(s) of evaluation of this end point: Endpoint 1: evaluated throughout the study until the accumulation of 945 adjudicated first MACE<br>Endpoint 2: Between week 28 and week 52<br><br>;Main Objective: •To compare daprodustat to recombinant human erthropoetin (rhEPO) for cardiovascular (CV) safety (non-inferiority)<br>•To compare daprodustat to recombinant human erthropoetin (rhEPO) for hemoglobin (Hgb) efficacy (non-inferiority)<br>;Secondary Objective: • To compare daprodustat to rhEPO on CV safety endpoints<br>• To compare daprodustat to rhEPO on the use of intravenous (IV) iron<br><br>;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)<br><br><br>

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, deep vein thrombosis or pulmonary embolism)<br>•MACE or a hospitalization for heart failure (HF)<br>•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).