Clinical trial NCT03029208: Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-in Incident Dialysis (ASCEND-ID)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anaemia
Keywords: Daprodustat, recombinant human erythropoietin, darbepoetin, anemia, chronic kidney disease, dialysis, ESRD
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-01-24
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Mean Change From Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)
timeFrame: Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)
Secondary outcomes:
measure: Average Monthly Intravenous Iron Dose (Milligrams) From Baseline to Week 52
timeFrame: Baseline (Day 1) to Week 52
measure: Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Blood Pressure (MAP) at Week 52
timeFrame: Baseline (Day 1) and Week 52
measure: Change From Baseline in SBP, DBP, MAP at End of Treatment
timeFrame: Baseline (Day 1) and end of treatment (last on-treatment value until Week 52)
measure: Blood Pressure (BP) Exacerbation Events Rate Per 100 Participant Years
timeFrame: Up to Week 52
measure: Number of Participants With at Least One Blood Pressure Exacerbation Event During Study
timeFrame: Up to Week 52
measure: Change From Baseline in Post-randomization Hgb at Week 52
timeFrame: Baseline (Day 1) and Week 52
measure: Number of Hgb Responders (Hgb in the Analysis Range of 10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)
timeFrame: Weeks 28 to 52
measure: Percentage of Time for Which Hgb Was Within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis
timeFrame: Weeks 28 to 52
measure: Percentage of Time for Which Hgb Was Within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Superiority Analysis
timeFrame: Weeks 28 to 52
measure: Number of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria
timeFrame: Up to Week 52
measure: Change From Baseline in Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52
timeFrame: Baseline (Day 1), Weeks 8, 12, 28 and 52
measure: Change From Baseline in Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52
timeFrame: Baseline (Day 1), Weeks 8, 12, 28 and 52
measure: Change From Baseline in SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52
timeFrame: Baseline (Day 1), Weeks 8, 12, 28 and 52
measure: Change From Baseline in Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 28, 52
timeFrame: Baseline (Day 1), Weeks 28 and 52
measure: Change From Baseline in Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 28, 52
timeFrame: Baseline (Day 1), Weeks 28 and 52
measure: Change From Baseline in Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52
timeFrame: Baseline (Day 1) and Week 52
measure: Change From Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52
timeFrame: Baseline (Day 1) and Week 52
measure: Change From Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52
timeFrame: Baseline (Day 1) and Week 52
measure: Change From Baseline in Patient Global Impression of Severity (PGI-S)
timeFrame: Baseline (Day 1), Weeks 8, 12, 28 and 52
measure: Plasma Concentration of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)
timeFrame: Pre-dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12
measure: Observed Concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)
timeFrame: Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12
measure: Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)
timeFrame: Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: GSK Investigational Site
state: California
city: Cerritos
country: United States
facility: GSK Investigational Site
state: California
city: Escondido
country: United States
facility: GSK Investigational Site
state: California
city: Glendale
country: United States
facility: GSK Investigational Site
state: California
city: La Palma
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Lynwood
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Whittier
country: United States
facility: GSK Investigational Site
state: California
city: Middlebury
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Coral Gables
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Augusta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Crystal Lake
country: United States
facility: GSK Investigational Site
state: Illinois
city: Fort Wayne
country: United States
facility: GSK Investigational Site
state: Indiana
city: Merrillville
country: United States
facility: GSK Investigational Site
state: Indiana
city: Michigan City
country: United States
facility: GSK Investigational Site
state: Indiana
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Baton Rouge
country: United States
facility: GSK Investigational Site
state: Louisiana
city: New Orleans
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Jackson
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: Buffalo
country: United States
facility: GSK Investigational Site
state: New York
city: Mineola
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Lufkin
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Hampton
country: United States
facility: GSK Investigational Site
state: Virginia
city: Ciudad Evita
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: La Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Morón
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Pergamino
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Pilar
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Formosa
country: Argentina
facility: GSK Investigational Site
city: Mendoza
country: Argentina
facility: GSK Investigational Site
city: San Miguel de Tucumán
country: Argentina
facility: GSK Investigational Site
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: St Albans
country: Australia
facility: GSK Investigational Site
state: Victoria
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Greenfield Park
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Duesseldorf
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Kaiserslautern
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Wiesbaden
country: Germany
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Chennai
country: India
facility: GSK Investigational Site
city: Delhi
country: India
facility: GSK Investigational Site
city: Gurgaon
country: India
facility: GSK Investigational Site
city: Kozhikode
country: India
facility: GSK Investigational Site
city: New Delhi
country: India
facility: GSK Investigational Site
city: Pune
country: India
facility: GSK Investigational Site
city: Secunderabad
country: India
facility: GSK Investigational Site
city: Thiruvananthapuram
country: India
facility: GSK Investigational Site
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Pavia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Cagliari
country: Italy
facility: GSK Investigational Site
state: Sardegna
city: Anyang-Si, Gyeonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Bucheon-si,
country: Korea, Republic of
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Suwon
country: Korea, Republic of
facility: GSK Investigational Site
city: Ipoh
country: Malaysia
facility: GSK Investigational Site
city: Kuala Lumpur
country: Malaysia
facility: GSK Investigational Site
city: Penang
country: Malaysia
facility: GSK Investigational Site
city: Torreon
country: Mexico
facility: GSK Investigational Site
state: Coahuila
city: Ciudad De México
country: Mexico
facility: GSK Investigational Site
state: Estado De México
city: Guadalajara.
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Zapopan
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Merida
country: Mexico
facility: GSK Investigational Site
state: Yucatán
city: Mérida
country: Mexico
facility: GSK Investigational Site
state: Yucatán
city: Aguascalientes
country: Mexico
facility: GSK Investigational Site
city: Tlalnepantla
country: Mexico
facility: GSK Investigational Site
city: Gdansk
country: Poland
facility: GSK Investigational Site
city: Kolo
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Ostroda
country: Poland
facility: GSK Investigational Site
city: Ostroleka
country: Poland
facility: GSK Investigational Site
city: Szczecin
country: Poland
facility: GSK Investigational Site
city: Irkutsk
country: Russian Federation
facility: GSK Investigational Site
city: Mytishchi
country: Russian Federation
facility: GSK Investigational Site
city: Omsk
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: St-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Volzhskiy
country: Russian Federation
facility: GSK Investigational Site
city: Cape Town.
country: South Africa
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Puerto Real
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Doncaster
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Middlesbrough
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Natale P, Palmer SC, Jaure A, Hodson EM, Ruospo M, Cooper TE, Hahn D, Saglimbene VM, Craig JC, Strippoli GF. Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.
citation: Singh AK, Cizman B, Carroll K, McMurray JJV, Perkovic V, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Wiecek A, Stankus N, Strutz F, Blackorby A, Cobitz AR, Meadowcroft AM, Paul G, Ranganathan P, Sedani S, Solomon S. Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022 Jun 1;182(6):592-602. doi: 10.1001/jamainternmed.2022.0605.