Last updated: 07/05/2021 11:00:16

Anemia Study in chronic kidney disease (CKD): Erythropoiesis via a Novel Prolyl hydroxylase inhibitor (PHI) Daprodustat-Blood Pressure (ASCEND-BP)

GSK study ID
205665
See study documents
Clinicaltrials.gov ID
NCT03029247
See results summary
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: A randomized, open-label study to evaluate the effect of daprodustat on blood pressure in subjects with anemia associated with chronic kidney disease on hemodialysis switched from a stable dose of an erythropoiesis-stimulating agent
Trial description: This will be an open-label, randomized, parallel-group study in hemodialysis-dependent (HD) participants with anemia associated with chronic kidney disease (CKD), designed to compare the effects of daprodustat to epoetin alfa on blood pressure (BP). Participants will be screened for eligibility within 7 and 30 days prior to erythropoesis-stimulating agent (ESA) washout. Following a 2-week ESA washout period, on Day 1 participants will be randomized 1:1 and stratified by prior ESA dose before they undergo Acute Challenge 1, a single dose challenge to compare the acute effects on BP of the highest planned once-daily maintenance dose of daprodustat (24 milligrams [mg]) to the highest starting dose of epoetin alfa (100 units/kilogram [U/kg]). This will be followed by an 8-week hemoglobin (Hgb)-maintenance period, where doses of either daprodustat or epoetin alfa will be administered and adjusted. At the end of Hgb maintenance period, on Day 57 an Acute Challenge 2 will be repeated utilizing the same treatment dose administered in Acute Challenge 1; there will be a follow-up visit within 14+/-3 days after completing treatment.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
None (Open Label)
Allocation:
Randomized
Primary outcomes:

Average of 6-hour post dose systolic blood pressure (SBP) at Day 57

Timeframe: Day 57

Secondary outcomes:

Average of 6-hour post dose SBP and diastolic BP (DBP) at Day 1 (millimeter of mercury [mmHg])

Timeframe: Day 1

Average of mean arterial blood pressure (MAP) over 6-hour post dose at Day 1

Timeframe: Day 1

Average heart rate over 6-hour post dose at Day 1

Timeframe: Day 1

Area under the effect curve (AUEC) of SBP over 24-hour post-dose at Day 1

Timeframe: Up to 24 hours post-dose at Day 1

AUEC of DBP over 24-hour post-dose at Day 1

Timeframe: Up to 24 hours post-dose at Day 1

AUEC of MAP over 24-hour post-dose at Day 1

Timeframe: Up to 24 hours post-dose at Day 1

AUEC of heart rate over 24-hour post-dose at Day 1

Timeframe: Up to 24 hours post-dose at Day 1

Average of 6- hour post dose DBP at Day 57

Timeframe: Day 57

Average of MAP over 6-hour post dosing at Day 57

Timeframe: Day 57

Average of heart rate over 6-hour post dosing at Day 57

Timeframe: Day 57

AUEC of SBP over 24-hour post-dose at Day 57

Timeframe: Up to 24 hours post-dose at Day 57

AUEC of DBP over 24-hour post-dose at Day 57

Timeframe: Up to 24 hours post-dose at Day 57

AUEC of MAP over 24-hour post-dose at Day 57

Timeframe: Up to 24 hours post-dose at Day 57

AUEC of heart rate over 24-hour post-dose at Day 57

Timeframe: Up to 24 hours post-dose at Day 57

Change from pre-dose in SBP, DBP, and MAP on Day 1 (mmHg)

Timeframe: Baseline (pre-dose, Day 1) and up to 24 hours post-dose on Day 1

Change from pre-dose in heart rate at each timepoint on Day 1

Timeframe: Baseline (pre-dose, Day 1) and up to 24 hours post-dose on Day 1

Maximum plasma concentration (Cmax) of daprodustat

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Cmax of metabolite GSK2391220

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Cmax of metabolite GSK2531403

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Cmax of metabolite GSK2487818

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Cmax of metabolite GSK2506102

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Cmax of metabolite GSK2531398

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Cmax of metabolite GSK2531401

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Time to occurrence of Cmax (Tmax) of daprodustat

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Tmax of metabolite GSK2391220

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Tmax of metabolite GSK2531403

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Tmax of metabolite GSK2487818

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Tmax of metabolite GSK2506102

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Tmax of metabolite GSK2531398

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Tmax of metabolite GSK2531401

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Terminal phase half-life (T1/2) of daprodustat

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

T1/2 of metabolite GSK2391220

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

T1/2 of metabolite GSK2531403

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

T1/2 of metabolite GSK2487818

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

T1/2 of metabolite GSK2506102

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

T1/2 of metabolite GSK2531398

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

T1/2 of metabolite GSK2531401

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Area under concentration-time curve from time zero to 24 hours (AUC [0-24]) of daprodustat

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

AUC(0-24) of metabolite GSK2391220

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

AUC(0-24) of metabolite GSK2531403

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

AUC(0-24) of metabolite GSK2487818

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

AUC(0-24) of metabolite GSK2506102

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

AUC(0-24) of metabolite GSK2531398

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

AUC(0-24) of metabolite GSK2531401

Timeframe: pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours post dose on Day 1 and Day 57 visit of the treatment period

Interventions:
Drug: Daprodustat
Drug: Epoetin alfa
Enrollment:
105
Observational study model:
Not applicable
Primary completion date:
2020-09-07
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Anaemia
Product
GSK584430, daprodustat
Collaborators
ERT, Q2 Solutions, Quintiles, HemoCue
Study date(s)
July 2017 to July 2020
Type
Interventional
Phase
2

Participation criteria

Sex
Female & Male
Age
40+ years
Accepts healthy volunteers
No
  • Inclusion Criteria
  • More than or equal to 40 years of age, at the time of signing the informed consent
Inclusion and exclusion criteria
Inclusion criteria:
  • Inclusion Criteria
  • More than or equal to 40 years of age, at the time of signing the informed consent
  • Stable Hgb 8.5 to 11.5 grams per deciliter (g/dL) inclusive.
  • Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three-to five-times weekly for at least 4 weeks prior to screening.
  • A single pool Kt/Vurea >=1.2 based on a historical value obtained within 3 months prior to screening in order to ensure the adequacy of dialysis. If Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio should be at least 65 percent (%).
  • Treated with an ESA (epoetins or their biosimilars, darbepoetin, or methoxy polyethylene glycol [PEG]-epoetin beta) for at least 4 weeks prior to screening.
  • Participants may be on stable (<=50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period) maintenance oral or intravenous (IV; <=100 mg/week) iron supplementation. If participants are on oral or IV iron, then doses must be stable for the 4 weeks prior to Washout.
  • Weight: Mid-week weight change between dialysis treatments <5% as assessed post-dialysis at the Screening and Washout visits.
  • On at least 1 antihypertensive medication (excluding diuretics) and on that same medication and the same dose for at least 1 week prior to Washout.
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and the protocol.
  • Willing and able to wear ABPM device for at least 25 hours on two separate sessions. Exclusion Criteria
  • Planned change from HD to peritoneal dialysis within the study time period, or on home dialysis.
  • Planned for kidney transplant within the 16 weeks following the Screening visit.
  • An epoetin alfa dose of >=360 U/kg/week IV or >=250 U/kg/week subcutaneous (SC), or darbepoetin dose of >=1.8 micrograms (μg)/kg/week IV or SC, or methoxy PEG-epoetin beta dose of >=2.2 μg/kg/week within the 8 weeks prior to screening through Week -4.
  • Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) within the 4 weeks prior to the Washout.
  • Occurrence of myocardial infarction or acute coronary syndrome within 3 months prior to Washout.
  • Stroke or transient ischemic attack within 3 months prior to Washout.
  • Chronic Class 4 heart failure, as defined by the New York Heart Association functional classification system diagnosed prior to Washout.
  • QT interval corrected for heart rate using Bazett’s formula (QTcB) >500 milliseconds (msec), or QTcB >530 msec in participants with Bundle Branch Block. There is no QTc exclusion for participants with a predominantly paced rhythm.
  • Resting post dialysis SBP >160 millimeters of mercury (mmHg); or DBP >100 mmHg at screening or uncontrolled hypertension as determined by the investigator.
  • Presence of atrial fibrillation.
  • Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) diagnosed prior to Washout.
  • History of bone marrow aplasia or pure red cell aplasia.
  • Other causes of anemia including Pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.
  • Alanine transaminase (ALT) >2 times upper limit of normal (ULN) (screening only) or Bilirubin >1.5 times ULN (screening only) 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.
  • Major surgery (excluding vascular access surgery) within the 3 months prior to Washout or planned during the study.
  • Blood transfusion within the 8 weeks prior to Washout or an anticipated need for blood transfusion during the study.
  • Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding within the 8 weeks prior to Washout.
  • Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Washout.
  • History of malignancy within the two years prior to screening through Day 1 or currently receiving treatment for cancer, or has a known complex kidney cyst (e.g., Bosniak Category IIF, III or IV) >=3 centimeters.
  • Participants with an upper arm diameter which cannot be measured by oscillometer/ sphygmomanometer cuff or for whom BP cannot be measured in the opposite arm of current vascular access.
  • History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.
  • Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until Washout.
  • The participant has participated in a clinical trial and has received an experimental investigational product within the 30 days prior to Day 1 or within 5 half lives of the investigational product prior to screening, whichever is longer.
  • Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
  • A female participant is pregnant (as confirmed by a positive serum human chorionic gonadotrophin test for females of reproductive potential only), participant is breastfeeding, or participant is of reproductive potential and does not agree to follow one of the pre-specified contraceptive options
  • Vitamin B12 at or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks, following treatment).
  • Folate at <2.0 nanograms/milliliter (ng/mL) (4.5 Nanomoles per Liter) (may rescreen in a minimum of 4 weeks, following treatment).
  • Ferritin at <100 ng/mL
  • Transferrin saturation at <20%.

Trial location(s)

Location
Status
Contact us
Contact us
Location
GSK Investigational Site
Chicago, Illinois, United States, 60643
Status
Study Complete
Contact us
Location
GSK Investigational Site
DeLand, Florida, United States, 32720
Status
Study Complete
Contact us
Location
GSK Investigational Site
La Mesa, California, United States, 91942
Status
Study Complete
Contact us
Location
GSK Investigational Site
Lakewood, Colorado, United States, 80228
Status
Study Complete
Contact us
Location
GSK Investigational Site
Minneapolis, Minnesota, United States, 55404
Status
Study Complete
Contact us
Location
GSK Investigational Site
Orlando, Florida, United States, 32809
Status
Study Complete
Contact us
Location
GSK Investigational Site
San Antonio, Texas, United States, 78215
Status
Study Complete
Contact us
Location
GSK Investigational Site
Coral Gables, Florida, United States, 33134
Status
Study Complete
Contact us
Location
GSK Investigational Site
Miami, Florida, United States, 33133
Status
Study Complete
Contact us
Location
GSK Investigational Site
Hollywood, Florida, United States, 33024
Status
Study Complete
Contact us
Location
GSK Investigational Site
Spartanburg, South Carolina, United States, 29301
Status
Study Complete
Contact us

Study documents

Protocol
Available language(s): English
Download document(s)
Statistical analysis plan
Available language(s): English
Download document(s)

If you wish to request for full study report, please contact - [email protected]

Results overview

Results posted on ClinicalTrials.gov

Recruitment status
Completed
Actual primary completion date
2020-09-07
Actual study completion date
2020-09-07

Plain language summaries

Summary of results in plain language
Available language(s): English, Spanish (United States)
Download document(s)

To view plain language summaries on trialsummaries.com click here.

Additional information about the trial

Additional information
Not applicable
Participate in clinical trial
Access to clinical trial data by researchers
Visit website