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

NCT03400033 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 2048372017-004372-56
• Study Type: interventional
• Target: 407
• Locations: 13 countries
• Sites: 91

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

Keywords

CKD, EPO, rhEPO, Hemodialysis dependent, Daprodustat

Outcome Measures

Primary Outcomes (1)

• Mean Change From Baseline in Hemoglobin Levels Over the Evaluation Period (Week 28 to Week 52)

  Blood samples were collected from participants for hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis, the missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputations. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region.

  Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)

Secondary Outcomes (12)

• Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant

  Day 1 to Week 52

• Change From Baseline in Hemoglobin Levels at Week 52

  Baseline (Pre-dose on Day 1) and Week 52

• Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)

  Week 28 to Week 52

• Number of Hemoglobin Responders in the Hemoglobin Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)

  Week 28 to Week 52

• Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria

  Up to Week 52

Study Arms (2)

Daprodustat

EXPERIMENTAL

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.

Drug: Daprodustat tablets; Drug: Saline vials or bags

Epoetin alfa

ACTIVE COMPARATOR

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.

Drug: Matching placebo tablets; Drug: Epoetin alfa vials

Interventions

Daprodustat tablets 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.

Daprodustat

Matching placebo tablets 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

Epoetin alfa vials DRUG

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

Epoetin alfa

Saline vials or bags DRUG

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

Daprodustat

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (91)

GSK Investigational Site

Mesa, Arizona, 85210, United States

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GSK Investigational Site

Fresno, California, 93720, United States

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Los Angeles, California, 90025, United States

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GSK Investigational Site

Paramount, California, 90723, United States

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Middlebury, Connecticut, 06762, United States

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Hollywood, Florida, 33024, United States

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Miami, Florida, 33169, United States

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Tampa, Florida, 33614, United States

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Macon, Georgia, 31201, United States

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Meridian, Idaho, 83642, United States

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Pittsfield, Massachusetts, 01201, United States

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Kansas City, Missouri, 64111, United States

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St Louis, Missouri, 63110, United States

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Albuquerque, New Mexico, 87109, United States

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College Point, New York, 11356, United States

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Winston-Salem, North Carolina, 27103, United States

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Oklahoma City, Oklahoma, 73116, United States

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Houston, Texas, 77004, United States

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Houston, Texas, 77099, United States

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Lufkin, Texas, 75904, United States

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Alexandria, Virginia, 22304, United States

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Hampton, Virginia, 23666, United States

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Norfolk, Virginia, 23510, United States

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Mar del Plata, Buenos Aires, 7600, Argentina

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Pergamino, Buenos Aires, B2700CPM, Argentina

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Sarandí, Buenos Aires, B1872EEB, Argentina

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Rosario, Santa Fe Province, 2000, Argentina

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Heidelberg, Victoria, 3084, Australia

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Parkville, Victoria, 3050, Australia

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Salvador, Estado de Bahia, 40415-065, Brazil

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Curitiba, Paraná, 80440-020, Brazil

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Passo Fundo, Rio Grande do Sul, 99010-080, Brazil

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Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

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São José do Rio Preto, São Paulo, 15090-000, Brazil

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Belo Horizonte, Minas Gerais, 30150-221, Brazil

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São Paulo, 04039-000, Brazil

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Oshawa, Ontario, L1G 2B9, Canada

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Bayonne, 64109, France

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Epagny Metz-Tessy, 74370, France

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Le Mans, 72037, France

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Nice, 06001, France

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Strasbourg, 67000, France

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Bologna, Emilia-Romagna, 40138, Italy

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Modena, Emilia-Romagna, 41124, Italy

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Pavia, Lombardy, 27100, Italy

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Verona, Veneto, 37126, Italy

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Katowice, 40-027, Poland

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Lodz, 92-213, Poland

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Sandomierz, 27-600, Poland

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Tarnowskie Góry, 42-612, Poland

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Żyrardów, 96-300, Poland

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GSK Investigational Site

Constanța, 900591, Romania

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Reşiţa, 320166, Romania

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GSK Investigational Site

Kazan', 420012, Russia

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Kolomna, 140407, Russia

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Krasnodar, 350029, Russia

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Krasnogorsk, 143400, Russia

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Mytischi, 141009, Russia

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Novorossiysk, 353915, Russia

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Novosibirsk, 630087, Russia

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Omsk, 644111, Russia

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Orenburg, 460040, Russia

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GSK Investigational Site

Penza, 440034, Russia

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Podolsk, 142110, Russia

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Saint Petersburg, 193318, Russia

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GSK Investigational Site

Saint Petersburg, 194104, Russia

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Saint Petersburg, 194354, Russia

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Saint Petersburg, 196247, Russia

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Saint Petersburg, 197110, Russia

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Saint Petersburg, 197374, Russia

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Ufa, 450071, Russia

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Yaroslavl, 150062, Russia

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GSK Investigational Site

Anyang-Si, Gyeonggi-do, 14068, South Korea

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Busan, 49201, South Korea

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Goyang-si, Gyeonggi-do, 10326, South Korea

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Incheon, 405-760, South Korea

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Seoul, 07061, South Korea

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GSK Investigational Site

Seoul, 07441, South Korea

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GSK Investigational Site

Seoul, 134-727, South Korea

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GSK Investigational Site

Almería, 04009, Spain

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GSK Investigational Site

Badalona, 08916, Spain

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GSK Investigational Site

Barcelona, 08036, Spain

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GSK Investigational Site

Girona, 17007, Spain

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GSK Investigational Site

Granollers, Barcelona, 08041, Spain

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GSK Investigational Site

Madrid, 28100, Spain

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GSK Investigational Site

Manises (Valencia), 46940, Spain

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GSK Investigational Site

Sanlúcar de Barrameda (Cádiz), 11540, Spain

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Bradford, BD5 0NA, United Kingdom

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London, SE5 9RS, United Kingdom

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Sheffield, S5 7AU, United Kingdom

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GSK Investigational Site

Swansea, SA6 6NL, United Kingdom

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Related Publications (2)

• 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.

  PMID: 36005278 DERIVED

• 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.

  PMID: 35918106 DERIVED

MeSH Terms

Conditions

Anemia

Interventions

GSK1278863

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is a double-blind study, in which the subject, investigator, site staff and the sponsor will remain blinded to each subjects study treatment assignment throughout the course of the study, with the exception of a limited number of unblinded site staff who are necessary to maintain the blind, as well as a limited number of sponsor staff.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects will be randomized to receive either daprodustat or epoetin alfa in a parallel manner. .

Study Record Dates

• First Submitted: January 8, 2018
• First Posted: January 17, 2018
• Study Start: September 5, 2018
• Primary Completion: June 19, 2020
• Study Completion: June 19, 2020
• Last Updated: July 12, 2021
• Results First Posted: July 12, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

AU (2); RU (19); BR (7); CA (1); FR (5); IT (4); PL (5); RO (2); KR (7); ES (8); GB (4); AR (4); US (23)