Clinical trial NCT03409107: Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ)
Official title: A 28-week, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center, Study in Recombinant Human Erythropoietin (rhEPO) naïve Non-dialysis Participants With Anemia Associated With Chronic Kidney Disease to Evaluate the Efficacy, Safety and Effects on Quality of Life of Daprodustat Compared to Placebo
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anaemia
Keywords: Non-Dialysis
Anemia
Chronic kidney disease
Recombinant human erythropoietin naïve
Hemoglobin
Daprodustat
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-01-24
Enrollment: 614
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized to receive Daprodustat or placebo in a randomized manner.
Primary purpose: TREATMENT

Brief summary: The purpose of this multi-center study in non-dialysis participants with anemia associated with CKD is to evaluate safety, efficacy and quality of life of daprodustat compared to placebo.


Eligibility criteria: Inclusion Criteria:

* \>=18 years of age at the time of signing the informed consent.
* Have CKD, confirmed at screening: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by Estimated glomerular filtration rate (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) formula.
* Participants with Stable HemoCue Hgb from 8.5 to 10.5 at screening visit (Week -4) and from 8.5 to 10.0 g/dL at randomization (Day 1).
* Participants may receive up to one intravenous (IV) iron dose within the 8 weeks prior to screening and NO IV iron use between screening visit and randomization (Day 1).
* If needed, participant may be on stable maintenance oral iron supplementation. There should be \<50% change in overall dose and no change in type of iron prescribed in the 4 weeks prior to Day 1 randomization visit.
* Male and female participants are eligible. A female participant 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 WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 4 weeks after the last dose of study treatment.
* Capable of giving signed informed consent.

Exclusion Criteria:

* Participants who are on dialysis or clinical evidence of impending need to initiate dialysis within 180 days after randomization (Day 1).
* Planned living-related or living-unrelated kidney transplant within 28 weeks after randomization (Day 1).
* Transferrin saturation (TSAT) \<15 percent (Screening only).
* Ferritin \<50 nanograms per milliliter (ng/mL) (Screening only).
* History of rhEPO or rhEPO analogue use within the 8 weeks prior to screening and rhEPO use between screening and randomization (Day 1).
* History of transfusion within the 8 weeks prior to screening and transfusion between screening and randomization (Day 1).
* History of bone marrow aplasia or pure red cell aplasia (PRCA).
* Participants with Megaloblastic anemia (untreated pernicious anemia and folate deficiency), thalassemia major, sickle cell disease or myelodysplastic syndrome.
* Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal (GI) bleeding \<= 8 weeks prior to screening through to randomization (Day 1).
* History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
* Use of strong inhibitor of CYP2C8 (for example, gemfibrozil) or strong inducers of CYP2C8 (for example, rifampin/rifampicin).
* Ferric citrate use within 4 weeks prior to randomization (Day 1).
* Use of other investigational agent or device prior to screening through to randomization (Day 1).
* Any prior treatment with daprodustat for a treatment duration of \>30 days.
* MI or acute coronary syndrome within the 8 weeks prior to screening through to randomization. (Day 1).
* Stroke or transient ischemic attack within the 8 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.
* QT interval corrected by Bazett's formula (QTcB) \>500 milliseconds (msec) or QTcB \>530 msec in participants with bundle branch block. There is no corrected QT interval (QTc) exclusion for participants with a predominantly paced rhythm.
* Alanine transaminase (ALT) \>2x upper limit of normal (ULN) at screening (Week -4).
* Bilirubin \>1.5xULN at screening (Week -4).
* 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.
* 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 (for example, Bosniak Category II F, III or IV) \> 3 centimeters (cm).
* Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
* Current uncontrolled hypertension as determined by the investigator.

Primary outcomes:
measure: Mean Change in Hemoglobin From Baseline and Over the Evaluation Period (Mean Over Week 24 and 28)
timeFrame: Baseline (Day 1) and Week 24 to Week 28
Secondary outcomes:
measure: Percentage of Participants With Hemoglobin Increase of >=1.0 Grams Per Deciliter From Baseline to Evaluation Period
timeFrame: Baseline (Day 1) and Week 24 to Week 28
measure: Change From Baseline in Short Form-36 (SF-36) Questionnaire Vitality Domain Score by Traditional Scoring at Week 28
timeFrame: Baseline (Day 1) and Week 28
measure: Percentage of Participants With Hgb Response (Hgb in the 11-12 Grams/Deciliter Range) During Evaluation Period (Week 24 to Week 28 Inclusive)
timeFrame: Week 24 to Week 28
measure: Percentage of Time With Hgb Within the Target Range (11-12 Grams Per Deciliter) During Evaluation Period (Week 24 to Week 28 Inclusive) (Hodges-Lehmann Estimate)
timeFrame: Week 24 to Week 28
measure: Percentage of Time With Hgb Within the Target Range (11-12 Grams Per Deciliter) During Evaluation Period (Week 24 to Week 28 Inclusive) (Mann-Whitney Estimate)
timeFrame: Week 24 to Week 28
measure: Change From Baseline in Post-randomization Hgb at Week 28
timeFrame: Baseline (Day 1) and Week 28
measure: Rate of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria
timeFrame: Up to Week 28
measure: Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire
timeFrame: Baseline (Day 1) and Week 28
measure: Change From Baseline in Patient Global Impression of Severity (PGI-S)
timeFrame: Baseline (Day 1) and Week 28
measure: Change From Baseline in the SF-36 Physical Functioning Domain
timeFrame: Baseline (Day 1) and Week 28
measure: Change From Baseline of the SF-36 Individual Items in the Vitality Domain
timeFrame: Baseline (Day 1) and Week 28
measure: Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV)
timeFrame: Week 8, Week 12 and Week 28
measure: Change From Baseline in WPAI-ANS-CPV: Percent Time Missed From Work
timeFrame: Baseline (Day 1), Week 8, Week 12 and Week 28
measure: Change From Baseline in WPAI-ANS-CPV: Mean Hours Missed From Work in the Past 7 Days
timeFrame: Baseline (Day 1), Week 8, Week 12 and Week 28
measure: Change From Baseline in WPAI: Percent Impairment at Work
timeFrame: Baseline (Day 1), Week 8, Week 12 and Week 28
measure: Change From Baseline in WPAI: Percent Overall Work Impairment
timeFrame: Baseline (Day 1), Week 8, Week 12 and Week 28
measure: Change From Baseline in WPAI: Percent Regular Daily Activity Impairment
timeFrame: Baseline (Day 1), Week 8, Week 12 and Week 28
measure: Change From Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) Utility Score
timeFrame: Baseline (Day 1) and Week 28
measure: Change From Baseline in EuroQol Visual Analogue Scale (EQ-VAS) Score
timeFrame: Baseline (Day 1) and Week 28
measure: Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Pressure (MAP) at Week 28
timeFrame: Baseline (Day 1) and Week 28
measure: Percentage of Participants With at Least One Blood Pressure (BP) Exacerbation Event
timeFrame: Up to Week 28
Other outcomes:
Locations:
city: Homewood
country: United States
facility: GSK Investigational Site
state: Alabama
city: Little Rock
country: United States
facility: GSK Investigational Site
state: Arkansas
city: Downey
country: United States
facility: GSK Investigational Site
state: California
city: Fresno
country: United States
facility: GSK Investigational Site
state: California
city: Lynwood
country: United States
facility: GSK Investigational Site
state: California
city: Northridge
country: United States
facility: GSK Investigational Site
state: California
city: Northridge
country: United States
facility: GSK Investigational Site
state: California
city: Riverside
country: United States
facility: GSK Investigational Site
state: California
city: Salinas
country: United States
facility: GSK Investigational Site
state: California
city: Santa Ana
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Hartford
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Middlebury
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Coral Springs
country: United States
facility: GSK Investigational Site
state: Florida
city: Hollywood
country: United States
facility: GSK Investigational Site
state: Florida
city: Kissimmee
country: United States
facility: GSK Investigational Site
state: Florida
city: Lauderdale Lakes
country: United States
facility: GSK Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Adairsville
country: United States
facility: GSK Investigational Site
state: Georgia
city: Macon
country: United States
facility: GSK Investigational Site
state: Georgia
city: Macon
country: United States
facility: GSK Investigational Site
state: Georgia
city: Statesboro
country: United States
facility: GSK Investigational Site
state: Georgia
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Overland Park
country: United States
facility: GSK Investigational Site
state: Kansas
city: Buckley
country: United States
facility: GSK Investigational Site
state: Michigan
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Saint Clair Shores
country: United States
facility: GSK Investigational Site
state: Michigan
city: Brookhaven
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Rochester
country: United States
facility: GSK Investigational Site
state: New Hampshire
city: Asheville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Midwest City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Beaver
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Duncansville
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Scottdale
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Smithfield
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: West Reading
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Orangeburg
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Kingsport
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Memphis
country: United States
facility: GSK Investigational Site
state: Tennessee
city: DeSoto
country: United States
facility: GSK Investigational Site
state: Texas
city: El Paso
country: United States
facility: GSK Investigational Site
state: Texas
city: McAllen
country: United States
facility: GSK Investigational Site
state: Texas
city: Waxahachie
country: United States
facility: GSK Investigational Site
state: Texas
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: San Nicolas
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: GSK Investigational Site
state: Córdova
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Santa Fe
country: Argentina
facility: GSK Investigational Site
city: Sydney
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Heidelberg
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Parkville
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Murdoch
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Fitzroy
country: Australia
facility: GSK Investigational Site
city: Feira de Santana.
country: Brazil
facility: GSK Investigational Site
state: Bahia
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahia
city: Vitoria
country: Brazil
facility: GSK Investigational Site
state: Espírito Santo
city: Ribeirão Preto
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Santo André - SP
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Sao Jose do Rio Preto
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Sao Jose do Rio Preto
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: São Bernardo do Campo
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Victoria
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Brampton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Guelph
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Kitchener
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sudbury
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montréal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec city
country: Canada
facility: GSK Investigational Site
state: Quebec
city: St-Charles-Borromée
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Grenoble cedex 9
country: France
facility: GSK Investigational Site
city: Le Mans cedex 9
country: France
facility: GSK Investigational Site
city: Marseille cedex 5
country: France
facility: GSK Investigational Site
city: Melun
country: France
facility: GSK Investigational Site
city: Mulhouse cedex
country: France
facility: GSK Investigational Site
city: Nantes Cedex 1
country: France
facility: GSK Investigational Site
city: Nice Cedex 1
country: France
facility: GSK Investigational Site
city: Saint-Priest en Jarez
country: France
facility: GSK Investigational Site
city: Catanzaro
country: Italy
facility: GSK Investigational Site
state: Calabria
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Bologna
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Modena
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Pavia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Mestre
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Busan
country: Korea, Republic of
facility: GSK Investigational Site
city: Busan
country: Korea, Republic of
facility: GSK Investigational Site
city: Daegu-si
country: Korea, Republic of
facility: GSK Investigational Site
city: Daegu
country: Korea, Republic of
facility: GSK Investigational Site
city: Gyeonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Seongnam-si, Gyeonggi-do
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: Leon
country: Mexico
facility: GSK Investigational Site
state: Guanajuato
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Boca del Rio
country: Mexico
facility: GSK Investigational Site
state: Veracruz
city: Córdoba
country: Mexico
facility: GSK Investigational Site
state: Veracruz
city: Merida
country: Mexico
facility: GSK Investigational Site
state: Yucatán
city: Guadalajara
country: Mexico
facility: GSK Investigational Site
city: Merida
country: Mexico
facility: GSK Investigational Site
city: Veracruz
country: Mexico
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Ciechanow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Lublin
country: Poland
facility: GSK Investigational Site
city: Olawa
country: Poland
facility: GSK Investigational Site
city: Pleszew
country: Poland
facility: GSK Investigational Site
city: Sosnowiec
country: Poland
facility: GSK Investigational Site
city: Swidnik
country: Poland
facility: GSK Investigational Site
city: Szczecin
country: Poland
facility: GSK Investigational Site
city: Tczew
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Brasov
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Craiova
country: Romania
facility: GSK Investigational Site
city: Deva
country: Romania
facility: GSK Investigational Site
city: Oradea
country: Romania
facility: GSK Investigational Site
city: Targu Mures
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Izhevsk
country: Russian Federation
facility: GSK Investigational Site
city: Kaliningrad
country: Russian Federation
facility: GSK Investigational Site
city: Kemerovo
country: Russian Federation
facility: GSK Investigational Site
city: Krasnoyarsk
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Nizhniy Novgorod
country: Russian Federation
facility: GSK Investigational Site
city: Pyatigorsk
country: Russian Federation
facility: GSK Investigational Site
city: Pyatigorsk
country: Russian Federation
facility: GSK Investigational Site
city: Rostov-on-Don
country: Russian Federation
facility: GSK Investigational Site
city: Ryazan
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Stavropol
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Canterbury
country: United Kingdom
facility: GSK Investigational Site
state: Kent
city: Derby
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Peterborough
country: United Kingdom
facility: GSK Investigational Site
city: Plymouth
country: United Kingdom
facility: GSK Investigational Site
city: Shrewsbury
country: United Kingdom
facility: GSK Investigational Site
city: Swansea
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Johansen KL, Cobitz AR, Singh AK, Macdougall IC, Lopes RD, Obrador GT, Kovesdy CP, Israni R, Jha V, Okoro T, Sprys M, Jolly S, Lindsay AC, Bhatt P, Camejo RR, Keeley T, Cizman B, Wheeler DC. The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease. Kidney Int. 2023 Jun;103(6):1180-1192. doi: 10.1016/j.kint.2023.02.019. Epub 2023 Mar 2.
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.