Last updated: 07/17/2024 17:02:46
Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Non-Dialysis (ASCEND-ND)
EudraCT ID
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
Official title: A phase 3 randomized, open-label (sponsor-blind), active-controlled, parallel-group, multi-center, event driven study in non-dialysis subjects with anemia associated with chronic kidney disease to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa
Trial description: The purpose of this multi-center event-driven study in non-dialysis (ND) participants with anemia associated with chronic kidney disease (CKD) is to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
None (Open Label)
Allocation:
Randomized
Primary outcomes:
Time to the first occurrence of adjudicated major adverse cardiovascular event (MACE) (composite of all-cause mortality, non-fatal myocardial infarction (MI) and non-fatal stroke)
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Mean change in hemoglobin (Hgb) between baseline and efficacy period (EP) (mean over Weeks 28-52)
Timeframe: Baseline, up to and including Week 52
Secondary outcomes:
Time to first occurrence of adjudicated MACE
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of adjudicated MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism)
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of adjudicated MACE or a hospitalization for heart failure (HF)
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to progression of CKD
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of all-cause mortality, cardiovascular (CV) mortality, fatal or non-fatal MI, fatal or non-fatal stroke
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of MACE or hospitalization for HF (recurrent events analysis)
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of all-cause hospitalization
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of all cause hospital re-admission within 30 days
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of MACE or hospitalization for HF or thromboembolic events
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of hospitalization for HF
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of thromboembolic events
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to first occurrence of individual components of CKD progression
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Percentage of responders, defined as mean Hgb within the Hgb analysis range
Timeframe: Up to and including Week 52
Number of blood pressure (BP) exacerbation events per 100 patient years
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Percentage of participants with least one BP exacerbation event during study
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Number of participants with least one BP exacerbation event during study
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Time to stopping randomized treatment due to meeting rescue criteria
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Change from Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) score at Week 52
Timeframe: Baseline, up to and including Week 52
Change from Baseline in EQ-5D-5L visual analog scale (VAS) at Week 52
Timeframe: Baseline, up to and including Week 52
Time to first occurrence of CV death or non fatal MI
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Hgb change from baseline to Week 52
Timeframe: Baseline, up to and including Week 52
Number of responders, defined as mean Hgb within the Hgb analysis range
Timeframe: Up to and including Week 52
Percentage time for which Hgb is in analysis range during the EP (Week 28 to 52) and during the maintenance period (MP; Week 28 to end of trial)
Timeframe: Randomization (Day 1) to end of study (event-driven, up to 4.1 years)
Change from baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52 and at end of treatment
Timeframe: Baseline and up to 4.1 years)
Mean change in SF-36 Health Related Quality of Life (HRQOL) scores between Baseline and Weeks 8, 12, 28, 52, of particular interest are the changes from baseline in the vitality and physical functioning domains at Weeks 28 and 52
Timeframe: Baseline, up to and including Week 52
Change from Baseline by domain and overall symptom score on the CKD-Anemia Questionnaire (AQ) at Weeks 8, 12, 28, 52
Timeframe: Baseline, up to and including Week 52
Change from Baseline in Patient Global Impression of Severity Scale (PGI-S) at Week 8, 12, 28 and 52
Timeframe: Baseline, up to and including Week 52
Change from Baseline in estimated glomerular filtration rate (eGFR) at Week 52
Timeframe: Baseline and at Week 52
Interventions:
Enrollment:
3872
Primary completion date:
2021-19-04
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Ajay K. Singh, Kevin Carroll, John J. V. McMurray, Scott Solomon, Vivekanand Jha, Kirsten L. Johansen, Renato D. Lopes, Iain C. Macdougall, Gregorio T. Obrador, Sushrut S. Waikar, Christoph Wanner, David C. Wheeler, Andrzej Wiecek, Allison Blackorby, Borut Cizman, Alexander R. Cobitz, Rich Davies, Tara L. DiMino, Lata Kler, Amy M. Meadowcroft, Lin Taft, Vlado Perkovic for the ASCEND-ND Study Group. DAPRODUSTAT FOR THE TREATMENT OF ANEMIA IN PATIENTS NOT UNDERGOING DIALYSIS. N Engl J Med. 2021;
DOI: 10.1056/NEJMoa2113380
PMID: 34739196
Vlado Perkovic, Allison Blackorby, Borut Cizman, Kevin Carroll, Alexander R. Cobitz, Rich Davies, Tara L. DiMino, Vivekanand Jha, Kirsten L. Johansen, Renato D. Lopes, Lata Kler, Iain C. Macdougall, John McMurray, Amy M. Meadowcroft, Gregorio T. Obrador, Scott Solomon, Lin Taft, Christoph Wanner, Sushrut S. Waikar, David C. Wheeler, Andrzej Wiecek, Ajay Singh.The ASCEND-ND trial: Study design and participant characteristics.Nephrol Dial Transplant.2021; DOI: 10.1093/ndt/gfab318 PMID: 34865143
Medical condition
Anaemia
Product
daprodustat, darbepoetin alfa
Collaborators
Not applicable
Study date(s)
September 2016 to April 2021
Type
Interventional
Phase
3
Participation criteria
Sex
Female & Male
Age
18 - 99 Years
Accepts healthy volunteers
No
- Age: 18 to 99 years of age (inclusive)
- CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula.
- Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
- Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).
Inclusion and exclusion criteria
Inclusion criteria:
- Age: 18 to 99 years of age (inclusive)
- CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula.
- Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomization.
- For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL.
- >=80% and <=120% compliance with placebo during run-in period.
- Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions.
Exclusion criteria:
- Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1).
- Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1).
- Ferritin: <=100 nanograms (ng)/milliliter (mL) (<=100 micrograms/liter [L]) at screening.
- Transferrin saturation (TSAT) (screening only): <=20%.
- Aplasias: History of bone marrow aplasia or pure red cell aplasia.
- 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 <=4 weeks prior to screening through to randomization (Day 1).
- MI or acute coronary syndrome: <=4 weeks prior to screening through to randomization (Day 1).
- Stroke or transient ischemic attack: <=4 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: Current uncontrolled hypertension as determined by the investigator.
- Bazett’s corrected QT interval (QTcB) (Day 1): QTcB >500 millisecond (msec), or QTcB >530 msec in subjects with bundle branch block. There is no Q-T Interval Corrected for Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm.
- Alanine transaminase (ALT): >2x upper limit of normal (ULN) at screening.
- Bilirubin: >1.5xULN at screening.
- Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
- Malignancy: 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 (example [e.g.] Bosniak Category II F, III or IV) > 3 centimeter (cm); with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated >=4 weeks prior to screening.
- Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or darbepoetin alfa.
- Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
- Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer).
- Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of >30 days.
- Females only: Subject is pregnant [as confirmed by a positive urine human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options.
- Other Conditions: 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 darbepoetin alfa) or prevent understanding of the aims or investigational procedures or possible consequences of the study.
Trial location(s)
Location
GSK Investigational Site
Aguascalientes, Aguascalientes, Mexico, 20230
Status
Study Complete
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Study documents
Study report synopsis
Available language(s): English
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2021-19-04
Actual study completion date
2021-19-04
Plain language summaries
Summary of results in plain language
Available language(s): English, Spanish (Argentina), Dutch (Belgium), Portuguese (Brazil), Bulgarian, French (Canadian), Spanish (Columbia), Czech, Danish, Estonian, French, German, Greek, Chinese (Hong Kong), Hungarian, Hindi, Kannada, Marathi, Malayalam, Tamil (India), Telugu, Gujarati, Urdu, Hebrew, Russian (Israel), Arabic (Israel), Italian, Korean, Malay (Malaysia), Chinese (Malaysia), Spanish (Mexico), Dutch, Samoan, Tongan (New Zealand), Tagalog, Cebuano, Hiligaynon, Ilocano (Philippines), Polish, Portuguese (Native), Romanian, Russian, Afrikaans, Spanish, Catalan, Swedish, Chinese (Taiwan), Turkish, Thai, Russian (Ukraine), Ukrainian, Vietnamese, Spanish (United States), Malay (Singapore), Tamil (Singapore), Tamil (Malaysia)
To view plain language summaries on trialsummaries.com click here.
Additional information about the trial
Additional information
Not applicable
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