Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-in Incident Dialysis (ASCEND-ID)

NCT03029208 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 2014102016-000507-86
• Study Type: interventional
• Target: 312
• Locations: 15 countries
• Sites: 111

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.

Conditions

Anaemia

Keywords

Daprodustat, recombinant human erythropoietin, darbepoetin, anemia, chronic kidney disease, dialysis, ESRD

Outcome Measures

Primary Outcomes (1)

• Mean Change From Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)

  Blood samples were collected from participants for Hgb measurement. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb values were imputed using pre-specified multiple imputations. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. An analysis of covariance (ANCOVA) model including randomization stratification factors Baseline Hgb and treatment was performed to obtain a point estimate and two-sided 95 percent (%) confidence interval (CI) for the treatment difference (daprodustat-darbepoetin alfa).

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

Secondary Outcomes (22)

• Average Monthly Intravenous Iron Dose (Milligrams) From Baseline to Week 52

  Baseline (Day 1) to Week 52

• Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Blood Pressure (MAP) at Week 52

  Baseline (Day 1) and Week 52

• Change From Baseline in SBP, DBP, MAP at End of Treatment

  Baseline (Day 1) and end of treatment (last on-treatment value until Week 52)

• Blood Pressure (BP) Exacerbation Events Rate Per 100 Participant Years

  Up to Week 52

• Number of Participants With at Least One Blood Pressure Exacerbation Event During Study

  Up to Week 52

Study Arms (2)

Daprodustat treated anemic subjects

EXPERIMENTAL

Subjects will receive oral daprodustat once daily.

Drug: Daprodustat; Drug: Iron therapy

Darbepoetin alfa treated anemic subjects

ACTIVE COMPARATOR

Subjects will receive darbepoetin alfa subcutaneously or intravenously.

Drug: Darbepoetin alfa; Drug: Iron therapy

Interventions

Daprodustat DRUG

Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 4, 6, 8, or 10 mg of daprodustat. Doses of 12, 16, and 24 mg of daprodustat will be provided using multiples of these tablet strengths.

Daprodustat treated anemic subjects

Darbepoetin alfa DRUG

Darbepoetin alfa will be supplied as prefilled syringes (PFS) for SC/IV injection available in strengths: 20, 30, 40, 60, 80, 100 and 150 mcg.

Darbepoetin alfa treated anemic subjects

Iron therapy DRUG

Iron therapy will be administered if ferritin is \<=100 ng/mL and/or TSAT is \<=20%.

Daprodustat treated anemic subjects; Darbepoetin alfa treated anemic subjects

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (111)

GSK Investigational Site

Anaheim, California, 92801, United States

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GSK Investigational Site

Cerritos, California, 90703, United States

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GSK Investigational Site

Escondido, California, 92025, United States

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GSK Investigational Site

Glendale, California, 91204, United States

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GSK Investigational Site

La Palma, California, 90623, United States

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Los Angeles, California, 90022, United States

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Los Angeles, California, 90095, United States

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GSK Investigational Site

Lynwood, California, 90262, United States

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GSK Investigational Site

Sacramento, California, 95825, United States

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GSK Investigational Site

Whittier, California, 90603, United States

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GSK Investigational Site

Middlebury, Connecticut, 06762, United States

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Coral Gables, Florida, 33134, United States

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Miami, Florida, 33126, United States

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Miami, Florida, 33169, United States

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Augusta, Georgia, 30912, United States

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Chicago, Illinois, 60637, United States

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Crystal Lake, Illinois, 60014, United States

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Fort Wayne, Indiana, 46804, United States

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Merrillville, Indiana, 46410, United States

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Michigan City, Indiana, 46360, United States

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Iowa City, Iowa, 52242, United States

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Baton Rouge, Louisiana, 70809, United States

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New Orleans, Louisiana, 70112, United States

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Baltimore, Maryland, 21287, United States

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Jackson, Mississippi, 39216, 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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Brooklyn, New York, 11203, United States

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Buffalo, New York, 14215, United States

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Mineola, New York, 11501, United States

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New York, New York, 10029, United States

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The Bronx, New York, 10461, United States

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GSK Investigational Site

Houston, Texas, 77004, United States

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GSK Investigational Site

Lufkin, Texas, 75904, United States

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San Antonio, Texas, 78229, United States

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Hampton, Virginia, 23666, United States

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Ciudad Evita, Buenos Aires, B1778IFA, Argentina

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La Plata, Buenos Aires, B1902COS, Argentina

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Morón, Buenos Aires, B1708DPO, Argentina

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Pergamino, Buenos Aires, B2700CPM, Argentina

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Pilar, Buenos Aires, 1629, Argentina

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Buenos Aires, 1425, Argentina

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Formosa, P3600LLD, Argentina

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Mendoza, M5500AFA, Argentina

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San Miguel de Tucumán, T4000AHL, Argentina

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Adelaide, South Australia, 5000, Australia

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Melbourne, Victoria, 3004, Australia

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St Albans, Victoria, 3021, Australia

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London, Ontario, N6A 5A5, Canada

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Toronto, Ontario, M3M 0B2, Canada

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Greenfield Park, Quebec, J4V 2H1, Canada

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Düsseldorf, North Rhine-Westphalia, 40210, Germany

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Kaiserslautern, Rhineland-Palatinate, 67655, Germany

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Wiesbaden, 65191, Germany

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Bangalore, 560055, India

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Chennai, 600037, India

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Delhi, 110076, India

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GSK Investigational Site

Gūrgaon, 122001, India

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Kozhikode, 673008, India

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New Delhi, 110060, India

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Pune, 411004, India

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Secunderabad, 560020, India

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Thiruvananthapuram, 695011, India

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Genoa, Liguria, 16132, Italy

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Milan, Lombardy, 20153, Italy

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Pavia, Lombardy, 27100, Italy

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Cagliari, Sardinia, 09100, Italy

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George Town, 10990, Malaysia

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Ipoh, 30450, Malaysia

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Kuala Lumpur, 59100, Malaysia

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Torreón, Coahuila, 27000, Mexico

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Guadalajara, Jalisco, 44600, Mexico

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Zapopan, Jalisco, 45030, Mexico

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Ciudad de México, State of Mexico, 14000, Mexico

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Mérida, Yucatán, 97130, Mexico

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Mérida, Yucatán, CP 97070, Mexico

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Aguascalientes, 20259, Mexico

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GSK Investigational Site

Tlalnepantla, 54055, Mexico

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Gdansk, 80-952, Poland

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Koło, 62-600, Poland

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Krakow, 31-826, Poland

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Lodz, 92-213, Poland

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Lodz, 96-300, Poland

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GSK Investigational Site

Ostrołęka, 7410, Poland

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Ostróda, 14-100, Poland

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GSK Investigational Site

Szczecin, 70-780, Poland

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Irkutsk, 664049, Russia

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GSK Investigational Site

Mytishchi, 141007, Russia

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GSK Investigational Site

Omsk, 644112, Russia

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GSK Investigational Site

Saint Petersburg, 191104, Russia

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GSK Investigational Site

Saint Petersburg, 194354, Russia

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GSK Investigational Site

Saint Petersburg, 196247, Russia

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GSK Investigational Site

Saint Petersburg, 197110, Russia

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GSK Investigational Site

Smolensk, 214006, Russia

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GSK Investigational Site

Volzhskiy, 404120, Russia

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Cape Town, 7925, South Africa

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

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Bucheon-si, 14647, South Korea

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GSK Investigational Site

Incheon, 6510, South Korea

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GSK Investigational Site

Seoul, 05030, South Korea

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GSK Investigational Site

Seoul, 08308, South Korea

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GSK Investigational Site

Suwon, 16499, South Korea

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GSK Investigational Site

Badalona, 08916, Spain

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GSK Investigational Site

Barcelona, 08035, Spain

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GSK Investigational Site

Madrid, 28040, Spain

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GSK Investigational Site

Puerto Real, 11510, Spain

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GSK Investigational Site

Seville, 41009, Spain

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GSK Investigational Site

Birmingham, B9 5SS, United Kingdom

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GSK Investigational Site

Doncaster, DN2 5LT, United Kingdom

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GSK Investigational Site

London, SE5 9RS, United Kingdom

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GSK Investigational Site

Middlesbrough, TS4 3BW, 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

• 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.

  PMID: 35377393 DERIVED

MeSH Terms

Conditions

Anemia; Renal Insufficiency, Chronic; Kidney Failure, Chronic

Interventions

GSK1278863; Darbepoetin alfa

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythropoietin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Proteins; Amino Acids, Peptides, and Proteins

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: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 20, 2017
• First Posted: January 24, 2017
• Study Start: May 11, 2017
• Primary Completion: September 24, 2020
• Study Completion: September 24, 2020
• Last Updated: October 20, 2021
• Results First Posted: October 20, 2021

Record last verified: 2021-09

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, key secondary endpoints and safety data 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

ME (8); ZA (1); GB (4); AU (3); MY (3); RU (9); ES (5); CA (3); DE (3); IN (9); IT (4); US (36); KR (6); AR (9); PL (8)