Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD)

NCT ID: NCT03400033

Last Updated: 2021-07-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 407 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-05
• Study Completion Date: 2020-06-19

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.

Conditions

Anaemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Daprodustat

Subjects randomized to this arm will receive daprodustat tablets titrated doses from 2 to 48 milligrams orally three-times weekly along with saline by IV route for the 52 weeks treatment period.

Group Type: EXPERIMENTAL

Daprodustat tablets

Intervention Type: DRUG

Round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.

Saline vials or bags

Intervention Type: DRUG

0.9% sodium chloride saline vials or bags administered by the IV route.

Epoetin alfa

Subjects randomized to this arm will receive matching placebo tablets to daprodustat orally three-times weekly and Epoetin alfa by IV route for the 52 weeks treatment period.

Group Type: ACTIVE_COMPARATOR

Matching placebo tablets

Intervention Type: DRUG

Matching placebo to daprodustat tablets supplied as round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.

Epoetin alfa vials

Intervention Type: DRUG

Single-dose, preservative-free vials in unit dose strengths of 2000, 3000, 4000 and 10,000 Units/milliliter administered by the IV route.

Interventions

Daprodustat tablets

Round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.

Intervention Type: DRUG

Matching placebo tablets

Matching placebo to daprodustat tablets supplied as round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route.

Intervention Type: DRUG

Epoetin alfa vials

Single-dose, preservative-free vials in unit dose strengths of 2000, 3000, 4000 and 10,000 Units/milliliter administered by the IV route.

Intervention Type: DRUG

Saline vials or bags

0.9% sodium chloride saline vials or bags administered by the IV route.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 99 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Mesa, Arizona, United States

GSK Investigational Site

Fresno, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Paramount, California, United States

GSK Investigational Site

Middlebury, Connecticut, United States

GSK Investigational Site

Hollywood, Florida, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Tampa, Florida, United States

GSK Investigational Site

Macon, Georgia, United States

GSK Investigational Site

Meridian, Idaho, United States

GSK Investigational Site

Pittsfield, Massachusetts, United States

GSK Investigational Site

Kansas City, Missouri, United States

GSK Investigational Site

St Louis, Missouri, United States

GSK Investigational Site

Albuquerque, New Mexico, United States

GSK Investigational Site

College Point, New York, United States

GSK Investigational Site

Winston-Salem, North Carolina, United States

GSK Investigational Site

Oklahoma City, Oklahoma, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Houston, Texas, United States

GSK Investigational Site

Lufkin, Texas, United States

GSK Investigational Site

Alexandria, Virginia, United States

GSK Investigational Site

Hampton, Virginia, United States

GSK Investigational Site

Norfolk, Virginia, United States

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina

GSK Investigational Site

Pergamino, Buenos Aires, Argentina

GSK Investigational Site

Sarandí, Buenos Aires, Argentina

GSK Investigational Site

Rosario, Santa Fe Province, Argentina

GSK Investigational Site

Heidelberg, Victoria, Australia

GSK Investigational Site

Parkville, Victoria, Australia

GSK Investigational Site

Salvador, Estado de Bahia, Brazil

GSK Investigational Site

Curitiba, Paraná, Brazil

GSK Investigational Site

Passo Fundo, Rio Grande do Sul, Brazil

GSK Investigational Site

Porto Alegre, Rio Grande do Sul, Brazil

GSK Investigational Site

São José do Rio Preto, São Paulo, Brazil

GSK Investigational Site

Belo Horizonte, Minas Gerais, , Brazil

GSK Investigational Site

São Paulo, , Brazil

GSK Investigational Site

Oshawa, Ontario, Canada

GSK Investigational Site

Bayonne, , France

GSK Investigational Site

Epagny Metz-Tessy, , France

GSK Investigational Site

Le Mans, , France

GSK Investigational Site

Nice, , France

GSK Investigational Site

Strasbourg, , France

GSK Investigational Site

Bologna, Emilia-Romagna, Italy

GSK Investigational Site

Modena, Emilia-Romagna, Italy

GSK Investigational Site

Pavia, Lombardy, Italy

GSK Investigational Site

Verona, Veneto, Italy

GSK Investigational Site

Katowice, , Poland

GSK Investigational Site

Lodz, , Poland

GSK Investigational Site

Sandomierz, , Poland

GSK Investigational Site

Tarnowskie Góry, , Poland

GSK Investigational Site

Żyrardów, , Poland

GSK Investigational Site

Constanța, , Romania

GSK Investigational Site

Reşiţa, , Romania

GSK Investigational Site

Kazan', , Russia

GSK Investigational Site

Kolomna, , Russia

GSK Investigational Site

Krasnodar, , Russia

GSK Investigational Site

Krasnogorsk, , Russia

GSK Investigational Site

Mytischi, , Russia

GSK Investigational Site

Novorossiysk, , Russia

GSK Investigational Site

Novosibirsk, , Russia

GSK Investigational Site

Omsk, , Russia

GSK Investigational Site

Orenburg, , Russia

GSK Investigational Site

Penza, , Russia

GSK Investigational Site

Podolsk, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Saint Petersburg, , Russia

GSK Investigational Site

Ufa, , Russia

GSK Investigational Site

Yaroslavl, , Russia

GSK Investigational Site

Anyang-Si, Gyeonggi-do, , South Korea

GSK Investigational Site

Busan, , South Korea

GSK Investigational Site

Goyang-si, Gyeonggi-do, , South Korea

GSK Investigational Site

Incheon, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Seoul, , South Korea

GSK Investigational Site

Almería, , Spain

GSK Investigational Site

Badalona, , Spain

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Girona, , Spain

GSK Investigational Site

Granollers, Barcelona, , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Manises (Valencia), , Spain

GSK Investigational Site

Sanlúcar de Barrameda (Cádiz), , Spain

GSK Investigational Site

Bradford, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Sheffield, , United Kingdom

GSK Investigational Site

Swansea, , United Kingdom

Countries

United States; Argentina; Australia; Brazil; Canada; France; Italy; Poland; Romania; Russia; South Korea; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 36005278 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35918106 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-004372-56

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

204837

Identifier Type: -

Identifier Source: org_study_id