Clinical trial NCT03400033: Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD)
Official title: A Phase 3 Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study in Hemodialysis Participants With Anemia of Chronic Kidney Disease to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Recombinant Human Erythropoietin or Its Analogs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anaemia
Keywords: CKD, EPO, rhEPO, Hemodialysis dependent, Daprodustat
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2018-01-17
Enrollment: 407
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomized to receive either daprodustat or epoetin alfa in a parallel manner. .
Primary purpose: TREATMENT

Brief summary: This Phase 3 study in hemodialysis-dependent subjects with anemia will evaluate the efficacy and safety of daprodustat administered three-times weekly compared to epoetin alfa, the current standard of care. This study includes a 4 week Screening Period, a 52 week Treatment Period and a 4 to 6 week follow-up period. Each subject will remain in the study for up to 62 weeks. Approximately 402 subjects will be randomized to receive either daprodustat three times weekly or epoetin alfa three-times weekly or once weekly, depending on dose level.


Eligibility criteria: Inclusion Criteria:

* Subject must be 18 to 99 years of age inclusive, at the time of signing the informed consent.
* Use of any approved rhEPO or analog for at least 8 weeks prior to the screening visit and continuing during the screening period until randomization (Day 1).
* Hgb concentration (measured by HemoCue) within the following range: Week -4: Hgb 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). If Hgb is 11.6 to 11.9 grams/deciliter (7.2 to 7.4 millimoles/liter), up to two retests are allowed; the retest value must be between 8 to 11.5 grams/deciliter (5 to 7.1 millimoles/liter). Day 1: Hgb 8 to 11 grams/deciliter (5 to 6.8 millimoles/liter) and receiving at least the minimum rhEPO or analog dose 3. Hgb\>11 to 11.5 grams/deciliter (6.8 to 7.1 millimoles/liter) and receiving greater than the minimum rhEPO or analog dose 3.
* On hemodialysis (including hemofiltration or hemodiafiltration) \>90 days prior to screening and continuing during the screening period.
* On hemodialysis (in-center) \>=3 times per week.
* Male and female subjects are eligible. A female subject 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 A WOCBP who agrees to follow the contraceptive guidance from at least 28 days prior to first dose of study treatment and for at least 28 days after the last dose of study treatment.
* Capable of giving signed informed consent.
* In France, a subject will be eligible for inclusion in this study if he or she is either affiliated to or beneficiary of a social security category.

Exclusion Criteria:

* Planned living-related or living-unrelated kidney transplant within 52 weeks after randomization (Day 1).
* Ferritin: \<=100 nanograms/milliliter (\<=100 micrograms/liter), at screening.
* Transferrin saturation (TSAT): \<=20 percent, at screening. If TSAT is 18 to 20 percent, 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 percent to confirm eligibility.
* Aplasias: History of bone marrow aplasia or pure red cell aplasia.
* Conditions, other than anemia of CKD, which can affect erythropoiesis.
* Myocardial infarction (MI) or acute coronary syndrome within 8 weeks prior to screening through to randomization (Day 1).
* Stroke or transient ischemic attack within 8 weeks prior to screening through to randomization (Day 1).
* Heart failure (HF): Chronic Class IV HF, 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.
* Bazett's correction of QTc interval (QTcB): at Day 1: QTcB \>500 milliseconds, or QTcB \>530 milliseconds in subjects with bundle branch block. There is no QTc (corrected QT) exclusion for subjects with a predominantly ventricular paced rhythm.
* Liver Disease: presence of any one of the following liver-related laboratory values or conditions, at screening, is exclusionary: ALT \>2x upper limit of normal (ULN); Bilirubin \>1.5x ULN; or 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.
* Evidence of actively bleeding gastric, duodenal or esophageal ulcer disease OR clinically significant gastro intestinal bleeding \<= 8 weeks prior to screening through to randomization (Day 1).
* History of malignancy within 2 years prior to screening through to randomization (Day 1), currently receiving treatment for cancer, or complex kidney cyst (e.g., Bosniak Category IIF, III or IV) \>3 centimeters.
* Use of a strong inhibitor of Cytochrome P4502C8 \[CYP2C8\] (e.g. gemfibrozil) or a strong inducer of CYP2C8 (e.g. rifampin/rifampicin).
* History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product (daprodustat) or epoetin alfa.
* Use of another investigational agent within 30 days or within five half-lives of the investigational agent (whichever is longer) or currently participating in a study of an investigational device prior to screening through to randomization (Day 1).
* Any prior treatment with daprodustat for treatment duration of \>30 days.
* 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 (e.g. 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 Levels Over the 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: Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant
timeFrame: Day 1 to Week 52
measure: Change From Baseline in Hemoglobin Levels at Week 52
timeFrame: Baseline (Pre-dose on Day 1) and Week 52
measure: Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)
timeFrame: Week 28 to Week 52
measure: Number of Hemoglobin Responders in the Hemoglobin Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)
timeFrame: Week 28 to Week 52
measure: Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria
timeFrame: Up to Week 52
measure: Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52
timeFrame: Baseline (Week -4 ) and Week 52
measure: Change From Baseline in SBP, DBP and MAP at End of Treatment
timeFrame: Baseline (Week -4) and end of treatment (last on-treatment value until Week 52)
measure: Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years
timeFrame: Up to 52 weeks
measure: Number of Participants With at Least One BP Exacerbation Event During the Study
timeFrame: Up to 52 weeks
measure: Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S)
timeFrame: Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52
measure: Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)
timeFrame: Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52
measure: Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)
timeFrame: Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52
Other outcomes:
Locations:
city: Mesa
country: United States
facility: GSK Investigational Site
state: Arizona
city: Fresno
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Paramount
country: United States
facility: GSK Investigational Site
state: California
city: Middlebury
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facility: GSK Investigational Site
state: Connecticut
city: Hollywood
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facility: GSK Investigational Site
state: Florida
city: Miami
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facility: GSK Investigational Site
state: Florida
city: Tampa
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facility: GSK Investigational Site
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city: Macon
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facility: GSK Investigational Site
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city: Meridian
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city: Saint Louis
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city: Winston-Salem
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facility: GSK Investigational Site
state: North Carolina
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facility: GSK Investigational Site
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city: Houston
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facility: GSK Investigational Site
state: Texas
city: Houston
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state: Texas
city: Lufkin
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facility: GSK Investigational Site
state: Texas
city: Alexandria
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facility: GSK Investigational Site
state: Virginia
city: Hampton
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facility: GSK Investigational Site
state: Virginia
city: Norfolk
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facility: GSK Investigational Site
state: Virginia
city: Mar del Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Pergamino
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Sarandi
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Heidelberg
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Parkville
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Salvador
country: Brazil
facility: GSK Investigational Site
state: Bahia
city: Curitiba
country: Brazil
facility: GSK Investigational Site
state: Paraná
city: Passo Fundo
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Sao Jose do Rio Preto
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Belo Horizonte, Minas Gerais
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Oshawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Bayonne
country: France
facility: GSK Investigational Site
city: Epagny Metz-Tessy
country: France
facility: GSK Investigational Site
city: Le Mans
country: France
facility: GSK Investigational Site
city: Nice Cedex 1
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Bologna
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Modena
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Pavia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Verona
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Anyang-Si, Gyeonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Busan
country: Korea, Republic of
facility: GSK Investigational Site
city: Goyang-si, Gyeonggi-do
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: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Katowice
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Sandomierz
country: Poland
facility: GSK Investigational Site
city: Tarnowskie Gory
country: Poland
facility: GSK Investigational Site
city: Zyrardow
country: Poland
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Resita
country: Romania
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Kolomna
country: Russian Federation
facility: GSK Investigational Site
city: Krasnodar
country: Russian Federation
facility: GSK Investigational Site
city: Krasnogorsk
country: Russian Federation
facility: GSK Investigational Site
city: Mytischi
country: Russian Federation
facility: GSK Investigational Site
city: Novorossiysk
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Omsk
country: Russian Federation
facility: GSK Investigational Site
city: Orenburg
country: Russian Federation
facility: GSK Investigational Site
city: Penza
country: Russian Federation
facility: GSK Investigational Site
city: Podolsk
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: 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: Ufa
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Almeria
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Gerona
country: Spain
facility: GSK Investigational Site
city: Granollers, Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Manises (Valencia)
country: Spain
facility: GSK Investigational Site
city: Sanlúcar De Barrameda (Cádiz)
country: Spain
facility: GSK Investigational Site
city: Bradford
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
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: 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: Coyne DW, Singh AK, Lopes RD, Bailey CK, DiMino TL, Huang C, Connaire J, Rastogi A, Kim SG, Orias M, Shah S, Patel V, Cobitz AR, Wanner C. Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial. Clin J Am Soc Nephrol. 2022 Sep;17(9):1325-1336. doi: 10.2215/CJN.00550122. Epub 2022 Aug 2.