Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD)
Sponsor
GlaxoSmithKline (Industry)
Overall Status
Completed
CT.gov ID
NCT03400033
Collaborator
(none)
407
91
2
21.5
4.5
0.2
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
407 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Subjects will be randomized to receive either daprodustat or epoetin alfa in a parallel manner. .Subjects will be randomized to receive either daprodustat or epoetin alfa in a parallel manner. .
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
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.
Primary Purpose:
Treatment
Official Title:
A Phase 3 Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study in Hemodialysis Participants With Anemia of Chronic Kidney Disease to Evaluate the Efficacy, Safety and Pharmacokinetics of Three-times Weekly Dosing of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Recombinant Human Erythropoietin or Its Analogs
Actual Study Start Date
:
Sep 5, 2018
Actual Primary Completion Date
:
Jun 19, 2020
Actual Study Completion Date
:
Jun 19, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: 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.
Drug: Saline vials or bags
0.9% sodium chloride saline vials or bags administered by the IV route.
|
| Active Comparator: 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. |
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.
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.
|
Outcome Measures
Primary Outcome Measures
- Mean Change From Baseline in Hemoglobin Levels Over the Evaluation Period (Week 28 to Week 52) [Baseline (Pre-dose on Day 1) and 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.
Secondary Outcome Measures
- Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant [Day 1 to Week 52]
Average monthly IV iron dose (mg) per participant during Day 1 to Week 52 was determined by calculating the total IV iron dose per participant from Day 1 to Week 52 while the participant was on study treatment and dividing by (the number of days the participant was on study treatment divided by 30.4375 days). Analysis was performed using the ANCOVA model with terms for treatment, Baseline monthly IV iron dose, and region.
- Change From Baseline in Hemoglobin Levels at Week 52 [Baseline (Pre-dose on Day 1) and Week 52]
Blood samples were collected from participants for hemoglobin measurements. 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 post-randomization visit value minus Baseline value. Analysis was performed using a mixed model repeated measures (MMRM) model fitted to hemoglobin data collected after Baseline up to Week 52, excluding values collected during the stabilization period (Day 1 to Week 28). The model included factors for treatment, time, region, Baseline hemoglobin and Baseline hemoglobin by time and treatment by time interaction terms.
- 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]
Participants received treatment during the study to achieve or maintain hemoglobin level in the target range. Percentage of time for which hemoglobin level was maintained within the analysis range (10 to 11.5 grams/deciliter) has been presented.
- 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]
Mean hemoglobin during the evaluation period was defined as the mean of all evaluable hemoglobin values during the evaluation period (Week 28 to Week 52) including any evaluable unscheduled hemoglobin values that were taken during this time period. Hemoglobin responders were defined as the number of participants with a mean hemoglobin during the evaluation period that falls within the hemoglobin analysis range of 10-11.5 grams/deciliter.
- Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria [Up to Week 52]
Percentage of participants permanently stopping study treatment due to meeting rescue criteria has been presented.
- Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52 [Baseline (Week -4 ) and Week 52]
Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. 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 on-treatment visit value minus Baseline value. Analysis was performed using MMRM model with treatment group, time, region, Baseline value, Baseline value*time, treatment group*time as variables.
- Change From Baseline in SBP, DBP and MAP at End of Treatment [Baseline (Week -4) and end of treatment (last on-treatment value until Week 52)]
Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. 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 last on-treatment visit value minus Baseline value. Analysis was performed using ANCOVA model with terms for treatment group, region and Baseline value. Adjusted mean and standard error have been presented.
- Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years [Up to 52 weeks]
BP exacerbation event is defined (based on post-dialysis BP) as SBP >=25 mmHg increased from Baseline or SBP >=180 mmHg; or DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the Negative Binomial Model.
- Number of Participants With at Least One BP Exacerbation Event During the Study [Up to 52 weeks]
BP exacerbation (based on post-dialysis BP) is defined as: SBP >= 25 mmHg increased from Baseline or SBP >=180mmHg; or DBP >=15 mmHg increase from Baseline or DBP >=110 mmHg. Number of participants with at least 1 BP exacerbation event have been reported.
- Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S) [Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52]
The PGI-S is a 1-item questionnaire designed to assess participant's impression of disease severity of their anemia of Chronic kidney disease (CKD). It is measured on a 5-point disease severity scale ranging from 0 (absent) to 4 (very severe), higher score indicates more disease severity. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline in on-treatment PGI-S scores was defined as the on-treatment visit value minus Baseline value. Analysis was performed using MMRM model fitted from Baseline up to Week 52 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions.
- Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) [Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52]
Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13).
- Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) [Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52]
Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13).
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 99 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | GSK Investigational Site | Mesa | Arizona | United States | 85210 |
| 2 | GSK Investigational Site | Fresno | California | United States | 93720 |
| 3 | GSK Investigational Site | Los Angeles | California | United States | 90025 |
| 4 | GSK Investigational Site | Paramount | California | United States | 90723 |
| 5 | GSK Investigational Site | Middlebury | Connecticut | United States | 06762 |
| 6 | GSK Investigational Site | Hollywood | Florida | United States | 33024 |
| 7 | GSK Investigational Site | Miami | Florida | United States | 33169 |
| 8 | GSK Investigational Site | Tampa | Florida | United States | 33614 |
| 9 | GSK Investigational Site | Macon | Georgia | United States | 31201 |
| 10 | GSK Investigational Site | Meridian | Idaho | United States | 83642 |
| 11 | GSK Investigational Site | Pittsfield | Massachusetts | United States | 01201 |
| 12 | GSK Investigational Site | Kansas City | Missouri | United States | 64111 |
| 13 | GSK Investigational Site | Saint Louis | Missouri | United States | 63110 |
| 14 | GSK Investigational Site | Albuquerque | New Mexico | United States | 87109 |
| 15 | GSK Investigational Site | College Point | New York | United States | 11356 |
| 16 | GSK Investigational Site | Winston-Salem | North Carolina | United States | 27103 |
| 17 | GSK Investigational Site | Oklahoma City | Oklahoma | United States | 73116 |
| 18 | GSK Investigational Site | Houston | Texas | United States | 77004 |
| 19 | GSK Investigational Site | Houston | Texas | United States | 77099 |
| 20 | GSK Investigational Site | Lufkin | Texas | United States | 75904 |
| 21 | GSK Investigational Site | Alexandria | Virginia | United States | 22304 |
| 22 | GSK Investigational Site | Hampton | Virginia | United States | 23666 |
| 23 | GSK Investigational Site | Norfolk | Virginia | United States | 23510 |
| 24 | GSK Investigational Site | Mar del Plata | Buenos Aires | Argentina | 7600 |
| 25 | GSK Investigational Site | Pergamino | Buenos Aires | Argentina | B2700CPM |
| 26 | GSK Investigational Site | Sarandi | Buenos Aires | Argentina | B1872EEB |
| 27 | GSK Investigational Site | Rosario | Santa Fe | Argentina | 2000 |
| 28 | GSK Investigational Site | Heidelberg | Victoria | Australia | 3084 |
| 29 | GSK Investigational Site | Parkville | Victoria | Australia | 3050 |
| 30 | GSK Investigational Site | Salvador | Bahia | Brazil | 40415-065 |
| 31 | GSK Investigational Site | Curitiba | Paraná | Brazil | 80440-020 |
| 32 | GSK Investigational Site | Passo Fundo | Rio Grande Do Sul | Brazil | 99010-080 |
| 33 | GSK Investigational Site | Porto Alegre | Rio Grande Do Sul | Brazil | 90610-000 |
| 34 | GSK Investigational Site | Sao Jose do Rio Preto | São Paulo | Brazil | 15090-000 |
| 35 | GSK Investigational Site | Belo Horizonte, Minas Gerais | Brazil | 30150-221 | |
| 36 | GSK Investigational Site | São Paulo | Brazil | 04039-000 | |
| 37 | GSK Investigational Site | Oshawa | Ontario | Canada | L1G 2B9 |
| 38 | GSK Investigational Site | Bayonne | France | 64109 | |
| 39 | GSK Investigational Site | Epagny Metz-Tessy | France | 74370 | |
| 40 | GSK Investigational Site | Le Mans | France | 72037 | |
| 41 | GSK Investigational Site | Nice Cedex 1 | France | 06001 | |
| 42 | GSK Investigational Site | Strasbourg | France | 67000 | |
| 43 | GSK Investigational Site | Bologna | Emilia-Romagna | Italy | 40138 |
| 44 | GSK Investigational Site | Modena | Emilia-Romagna | Italy | 41124 |
| 45 | GSK Investigational Site | Pavia | Lombardia | Italy | 27100 |
| 46 | GSK Investigational Site | Verona | Veneto | Italy | 37126 |
| 47 | GSK Investigational Site | Anyang-Si, Gyeonggi-do | Korea, Republic of | 14068 | |
| 48 | GSK Investigational Site | Busan | Korea, Republic of | 49201 | |
| 49 | GSK Investigational Site | Goyang-si, Gyeonggi-do | Korea, Republic of | 10326 | |
| 50 | GSK Investigational Site | Incheon | Korea, Republic of | 405-760 | |
| 51 | GSK Investigational Site | Seoul | Korea, Republic of | 07061 | |
| 52 | GSK Investigational Site | Seoul | Korea, Republic of | 07441 | |
| 53 | GSK Investigational Site | Seoul | Korea, Republic of | 134-727 | |
| 54 | GSK Investigational Site | Katowice | Poland | 40-027 | |
| 55 | GSK Investigational Site | Lodz | Poland | 92-213 | |
| 56 | GSK Investigational Site | Sandomierz | Poland | 27-600 | |
| 57 | GSK Investigational Site | Tarnowskie Gory | Poland | 42-612 | |
| 58 | GSK Investigational Site | Zyrardow | Poland | 96-300 | |
| 59 | GSK Investigational Site | Constanta | Romania | 900591 | |
| 60 | GSK Investigational Site | Resita | Romania | 320166 | |
| 61 | GSK Investigational Site | Kazan | Russian Federation | 420012 | |
| 62 | GSK Investigational Site | Kolomna | Russian Federation | 140407 | |
| 63 | GSK Investigational Site | Krasnodar | Russian Federation | 350029 | |
| 64 | GSK Investigational Site | Krasnogorsk | Russian Federation | 143400 | |
| 65 | GSK Investigational Site | Mytischi | Russian Federation | 141009 | |
| 66 | GSK Investigational Site | Novorossiysk | Russian Federation | 353915 | |
| 67 | GSK Investigational Site | Novosibirsk | Russian Federation | 630087 | |
| 68 | GSK Investigational Site | Omsk | Russian Federation | 644111 | |
| 69 | GSK Investigational Site | Orenburg | Russian Federation | 460040 | |
| 70 | GSK Investigational Site | Penza | Russian Federation | 440034 | |
| 71 | GSK Investigational Site | Podolsk | Russian Federation | 142110 | |
| 72 | GSK Investigational Site | Saint-Petersburg | Russian Federation | 194354 | |
| 73 | GSK Investigational Site | Saint-Petersburg | Russian Federation | 197374 | |
| 74 | GSK Investigational Site | St-Petersburg | Russian Federation | 197110 | |
| 75 | GSK Investigational Site | St. Petersburg | Russian Federation | 193318 | |
| 76 | GSK Investigational Site | St. Petersburg | Russian Federation | 194104 | |
| 77 | GSK Investigational Site | St. Petersburg | Russian Federation | 196247 | |
| 78 | GSK Investigational Site | Ufa | Russian Federation | 450071 | |
| 79 | GSK Investigational Site | Yaroslavl | Russian Federation | 150062 | |
| 80 | GSK Investigational Site | Almeria | Spain | 04009 | |
| 81 | GSK Investigational Site | Badalona | Spain | 08916 | |
| 82 | GSK Investigational Site | Barcelona | Spain | 08036 | |
| 83 | GSK Investigational Site | Gerona | Spain | 17007 | |
| 84 | GSK Investigational Site | Granollers, Barcelona | Spain | 08041 | |
| 85 | GSK Investigational Site | Madrid | Spain | 28100 | |
| 86 | GSK Investigational Site | Manises (Valencia) | Spain | 46940 | |
| 87 | GSK Investigational Site | Sanlúcar De Barrameda (Cádiz) | Spain | 11540 | |
| 88 | GSK Investigational Site | Bradford | United Kingdom | BD5 0NA | |
| 89 | GSK Investigational Site | London | United Kingdom | SE5 9RS | |
| 90 | GSK Investigational Site | Sheffield | United Kingdom | S5 7AU | |
| 91 | GSK Investigational Site | Swansea | United Kingdom | SA6 6NL |
Sponsors and Collaborators
- GlaxoSmithKline
Investigators
- Study Director: GSK Clinical Trials, GlaxoSmithKline
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT03400033
Other Study ID Numbers:
- 204837
- 2017-004372-56
First Posted:
Jan 17, 2018
Last Update Posted:
Jul 12, 2021
Last Verified:
Jun 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by GlaxoSmithKline
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This was a multicenter study conducted at 90 centers in 13 countries. Participants were randomized to receive either Daprodustat or Epoetin alfa. |
|---|---|
| Pre-assignment Detail | A total of 595 participants were screened, of which 188 were screen failures. A total of 407 participants were enrolled in the study. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Period Title: Overall Study | ||
| STARTED | 270 | 137 |
| COMPLETED | 269 | 135 |
| NOT COMPLETED | 1 | 2 |
Baseline Characteristics
| Arm/Group Title | Daprodustat | Epoetin Alfa | Total |
|---|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. | Total of all reporting groups |
| Overall Participants | 270 | 137 | 407 |
| Age, Customized (Count of Participants) | |||
| 19-64 Years |
167
61.9%
|
96
70.1%
|
263
64.6%
|
| >= 65 Years |
103
38.1%
|
41
29.9%
|
144
35.4%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
121
44.8%
|
56
40.9%
|
177
43.5%
|
| Male |
149
55.2%
|
81
59.1%
|
230
56.5%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| BLACK OR AFRICAN AMERICAN |
49
18.1%
|
32
23.4%
|
81
19.9%
|
| AMERICAN INDIAN OR ALASKAN NATIVE |
1
0.4%
|
1
0.7%
|
2
0.5%
|
| ASIAN - CENTRAL/SOUTH ASIAN HERITAGE |
1
0.4%
|
0
0%
|
1
0.2%
|
| ASIAN - EAST ASIAN HERITAGE |
16
5.9%
|
9
6.6%
|
25
6.1%
|
| ASIAN - SOUTH EAST ASIAN HERITAGE |
3
1.1%
|
0
0%
|
3
0.7%
|
| NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER |
1
0.4%
|
0
0%
|
1
0.2%
|
| WHITE - ARABIC/NORTH AFRICAN HERITAGE |
1
0.4%
|
4
2.9%
|
5
1.2%
|
| WHITE - WHITE/CAUCASIAN/EUROPEAN HERITAGE |
193
71.5%
|
90
65.7%
|
283
69.5%
|
| MIXED WHITE RACE |
1
0.4%
|
0
0%
|
1
0.2%
|
| MIXED RACE |
1
0.4%
|
1
0.7%
|
2
0.5%
|
| UNKNOWN |
3
1.1%
|
0
0%
|
3
0.7%
|
Outcome Measures
| Title | Mean Change From Baseline in Hemoglobin Levels Over the Evaluation Period (Week 28 to Week 52) |
|---|---|
| Description | 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. |
| Time Frame | Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (Intent-to-treat [ITT]) Population comprised of all randomized participants. Any participant who received a treatment randomization number was considered to have been randomized. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 137 |
| Least Squares Mean (Standard Error) [Grams per deciliter (g/dL)] |
-0.04
(0.045)
|
0.02
(0.066)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority was to be established if the lower limit of the two-sided 95 percent (%) confidence interval (CI) for the treatment difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Least square (LS) mean difference |
| Estimated Value | -0.05 | |
| Confidence Interval |
(2-Sided) 95% -0.21 to 0.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant |
|---|---|
| Description | Average monthly IV iron dose (mg) per participant during Day 1 to Week 52 was determined by calculating the total IV iron dose per participant from Day 1 to Week 52 while the participant was on study treatment and dividing by (the number of days the participant was on study treatment divided by 30.4375 days). Analysis was performed using the ANCOVA model with terms for treatment, Baseline monthly IV iron dose, and region. |
| Time Frame | Day 1 to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 136 |
| Least Squares Mean (Standard Error) [Milligrams] |
98.11
(11.049)
|
106.23
(15.569)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3354 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -8.12 | |
| Confidence Interval |
(2-Sided) 95% -45.66 to 29.41 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Hemoglobin Levels at Week 52 |
|---|---|
| Description | Blood samples were collected from participants for hemoglobin measurements. 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 post-randomization visit value minus Baseline value. Analysis was performed using a mixed model repeated measures (MMRM) model fitted to hemoglobin data collected after Baseline up to Week 52, excluding values collected during the stabilization period (Day 1 to Week 28). The model included factors for treatment, time, region, Baseline hemoglobin and Baseline hemoglobin by time and treatment by time interaction terms. |
| Time Frame | Baseline (Pre-dose on Day 1) and Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 252 | 128 |
| Least Squares Mean (Standard Error) [Grams per deciliter] |
-0.03
(0.069)
|
0.11
(0.098)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -0.14 | |
| Confidence Interval |
(2-Sided) 95% -0.37 to 0.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52) |
|---|---|
| Description | Participants received treatment during the study to achieve or maintain hemoglobin level in the target range. Percentage of time for which hemoglobin level was maintained within the analysis range (10 to 11.5 grams/deciliter) has been presented. |
| Time Frame | Week 28 to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with at least one evaluable hemoglobin value during the evaluation period were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 215 | 107 |
| Median (Inter-Quartile Range) [Percentage of days] |
70.83
|
61.76
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was above the non-inferiority margin of - 15%. | |
| Statistical Test of Hypothesis | p-Value | 0.0034 |
| Comments | ||
| Method | Van Elteren's test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Median Difference (Final Values) |
| Estimated Value | 11.18 | |
| Confidence Interval |
(2-Sided) 95% 2.83 to 19.56 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hodges-Lehmann Estimate of Treatment Difference has been reported. | |
| Title | Number of Hemoglobin Responders in the Hemoglobin Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52) |
|---|---|
| Description | Mean hemoglobin during the evaluation period was defined as the mean of all evaluable hemoglobin values during the evaluation period (Week 28 to Week 52) including any evaluable unscheduled hemoglobin values that were taken during this time period. Hemoglobin responders were defined as the number of participants with a mean hemoglobin during the evaluation period that falls within the hemoglobin analysis range of 10-11.5 grams/deciliter. |
| Time Frame | Week 28 to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with at least one evaluable hemoglobin value during the evaluation period were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 215 | 107 |
| Count of Participants [Participants] |
172
63.7%
|
68
49.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0007 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in response rate |
| Estimated Value | 0.1645 | |
| Confidence Interval |
(2-Sided) 95% 0.06 to 0.27 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria |
|---|---|
| Description | Percentage of participants permanently stopping study treatment due to meeting rescue criteria has been presented. |
| Time Frame | Up to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 137 |
| Number [Percentage of participants] |
2.2
0.8%
|
2.2
1.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5308 |
| Comments | ||
| Method | Wald test | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.06 | |
| Confidence Interval |
(2-Sided) 95% 0.26 to 4.22 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio is estimated using a Cox proportional hazard regression model adjusted for treatment group and region. | |
| Title | Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52 |
|---|---|
| Description | Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. 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 on-treatment visit value minus Baseline value. Analysis was performed using MMRM model with treatment group, time, region, Baseline value, Baseline value*time, treatment group*time as variables. |
| Time Frame | Baseline (Week -4 ) and Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 266 | 133 |
| SBP |
-3.18
(1.470)
|
0.55
(2.252)
|
| DBP |
-2.52
(0.764)
|
-0.29
(1.176)
|
| MAP |
-2.72
(0.907)
|
-0.12
(1.389)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.083 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -3.73 | |
| Confidence Interval |
(2-Sided) 95% -9.03 to 1.56 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | SBP | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.057 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -2.23 | |
| Confidence Interval |
(2-Sided) 95% -4.99 to 0.54 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | DBP | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.059 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -2.60 | |
| Confidence Interval |
(2-Sided) 95% -5.86 to 0.67 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MAP | |
| Title | Change From Baseline in SBP, DBP and MAP at End of Treatment |
|---|---|
| Description | Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. 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 last on-treatment visit value minus Baseline value. Analysis was performed using ANCOVA model with terms for treatment group, region and Baseline value. Adjusted mean and standard error have been presented. |
| Time Frame | Baseline (Week -4) and end of treatment (last on-treatment value until Week 52) |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 136 |
| SBP |
-1.4
(1.24)
|
-0.9
(1.75)
|
| DBP |
-1.8
(0.66)
|
-0.8
(0.93)
|
| MAP |
-1.7
(0.78)
|
-0.8
(1.09)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.407 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.50 | |
| Confidence Interval |
(2-Sided) 95% -4.73 to 3.72 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | SBP | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.179 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -1.05 | |
| Confidence Interval |
(2-Sided) 95% -3.29 to 1.19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | DBP | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.261 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Net) |
| Estimated Value | -0.86 | |
| Confidence Interval |
(2-Sided) 95% -3.50 to 1.78 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | MAP | |
| Title | Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years |
|---|---|
| Description | BP exacerbation event is defined (based on post-dialysis BP) as SBP >=25 mmHg increased from Baseline or SBP >=180 mmHg; or DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the Negative Binomial Model. |
| Time Frame | Up to 52 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 136 |
| Number (95% Confidence Interval) [Events per 100 participant years] |
250.45
|
356.91
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0093 |
| Comments | ||
| Method | Negative binomial model | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of exacerbation rate |
| Estimated Value | 0.70 | |
| Confidence Interval |
(2-Sided) 95% 0.52 to 0.94 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With at Least One BP Exacerbation Event During the Study |
|---|---|
| Description | BP exacerbation (based on post-dialysis BP) is defined as: SBP >= 25 mmHg increased from Baseline or SBP >=180mmHg; or DBP >=15 mmHg increase from Baseline or DBP >=110 mmHg. Number of participants with at least 1 BP exacerbation event have been reported. |
| Time Frame | Up to 52 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed. |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 136 |
| Count of Participants [Participants] |
151
55.9%
|
91
66.4%
|
| Title | Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S) |
|---|---|
| Description | The PGI-S is a 1-item questionnaire designed to assess participant's impression of disease severity of their anemia of Chronic kidney disease (CKD). It is measured on a 5-point disease severity scale ranging from 0 (absent) to 4 (very severe), higher score indicates more disease severity. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline in on-treatment PGI-S scores was defined as the on-treatment visit value minus Baseline value. Analysis was performed using MMRM model fitted from Baseline up to Week 52 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions. |
| Time Frame | Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles). |
| Arm/Group Title | Daprodustat | Epoetin Alfa |
|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. |
| Measure Participants | 270 | 137 |
| Week 8; n=248, 126 |
-0.10
(0.048)
|
0.05
(0.068)
|
| Week 12; n=243, 120 |
-0.13
(0.050)
|
-0.01
(0.071)
|
| Week 28; n=211, 106 |
-0.07
(0.054)
|
0.03
(0.077)
|
| Week 52; n=170, 85 |
-0.11
(0.063)
|
0.04
(0.088)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0323 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -0.15 | |
| Confidence Interval |
(2-Sided) 95% -0.32 to 0.01 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Week 8 | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0921 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -0.12 | |
| Confidence Interval |
(2-Sided) 95% -0.29 to 0.06 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Week 12 | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1291 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -0.11 | |
| Confidence Interval |
(2-Sided) 95% -0.29 to 0.08 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Week 28 | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Daprodustat, Epoetin Alfa |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0859 |
| Comments | ||
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -0.15 | |
| Confidence Interval |
(2-Sided) 95% -0.36 to 0.06 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Week 52 | |
| Title | Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) |
|---|---|
| Description | Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13). |
| Time Frame | Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic Population comprised of all randomized participants for whom a post-Baseline pharmacokinetic sample was obtained and analyzed. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles). |
| Arm/Group Title | Daprodustat 2 mg | Daprodustat 4 mg | Daprodustat 8 mg | Daprodustat 12 mg | Daprodustat 16 mg | Daprodustat 20 mg | Daprodustat 24 mg | Daprodustat 32 mg | Daprodustat 48 mg |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets 2 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 4 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit. |
| Measure Participants | 8 | 20 | 51 | 59 | 45 | 28 | 16 | 3 | 3 |
| Daprodustat; n=1, 2, 10, 18, 14, 9, 6, 3, 2 |
6.2400
(NA)
|
1.1207
(494.71)
|
0.1786
(77.35)
|
0.3727
(277.88)
|
0.3443
(100.78)
|
0.3871
(161.05)
|
0.1621
(42.17)
|
0.2768
(140.82)
|
0.3486
(68.34)
|
| GSK2391220; n=4, 17,42, 57, 40, 25, 16, 3, 3 |
0.8623
(241.17)
|
0.5893
(255.59)
|
0.6341
(123.92)
|
1.1572
(184.51)
|
1.1654
(191.57)
|
1.1792
(168.59)
|
1.4987
(136.35)
|
1.6974
(6.82)
|
1.3531
(19.28)
|
| GSK2487818; n=1, 4, 5, 20, 14, 7, 4, 3, 2 |
0.3620
(NA)
|
0.2867
(111.67)
|
0.1594
(16.91)
|
0.2996
(105.55)
|
0.3027
(69.12)
|
0.2868
(109.23)
|
0.2585
(30.72)
|
0.2414
(29.66)
|
0.2111
(80.56)
|
| GSK2506102; n=4, 17, 45, 59, 43, 27, 16, 3, 3 |
0.9951
(122.94)
|
0.8372
(121.27)
|
0.9634
(95.99)
|
1.5100
(105.50)
|
1.5480
(122.95)
|
1.6555
(133.94)
|
3.2099
(67.36)
|
1.6892
(30.44)
|
1.8595
(48.36)
|
| GSK2506104; n=6, 17, 45, 59, 43, 27, 16, 3, 3 |
0.9750
(408.49)
|
1.9588
(163.27)
|
2.0381
(124.74)
|
3.5141
(136.72)
|
3.3872
(182.27)
|
3.6000
(173.62)
|
6.5730
(99.82)
|
4.2068
(15.44)
|
4.1894
(23.78)
|
| GSK2531398; n=2, 7, 22, 41, 33, 20, 15, 3, 3 |
1.1778
(20.55)
|
0.6069
(271.48)
|
0.2362
(76.76)
|
0.4444
(144.99)
|
0.3917
(169.77)
|
0.3728
(197.51)
|
0.3992
(153.15)
|
0.3963
(16.52)
|
0.2280
(56.68)
|
| GSK2531401; n=6, 17, 45, 59, 44, 27, 16, 3, 3 |
1.4466
(190.80)
|
3.5579
(102.68)
|
4.0910
(148.03)
|
6.8137
(102.34)
|
5.6037
(130.97)
|
8.4611
(128.74)
|
11.7372
(65.37)
|
6.0453
(140.63)
|
16.2584
(41.06)
|
| Title | Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) |
|---|---|
| Description | Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13). |
| Time Frame | Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic Population. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles). |
| Arm/Group Title | Daprodustat 2 mg | Daprodustat 4 mg | Daprodustat 8 mg | Daprodustat 12 mg | Daprodustat 16 mg | Daprodustat 20 mg | Daprodustat 24 mg | Daprodustat 32 mg | Daprodustat 48 mg |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants received daprodustat tablets 2 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 4 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit. | Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit. |
| Measure Participants | 8 | 20 | 51 | 59 | 45 | 28 | 16 | 3 | 3 |
| Daprodustat; n=8, 20, 49, 57, 45, 28, 16, 3, 3 |
44.5832
(227.65)
|
51.9261
(227.59)
|
113.4049
(179.69)
|
143.8790
(233.09)
|
126.6824
(288.50)
|
212.5087
(152.47)
|
290.3163
(87.39)
|
197.7071
(36.53)
|
310.1938
(190.69)
|
| GSK2391220; n=8, 19, 50, 59, 45, 28, 16, 3, 3 |
2.6298
(60.93)
|
4.0224
(134.91)
|
6.3826
(198.78)
|
8.9535
(126.76)
|
9.5131
(167.92)
|
11.8995
(172.35)
|
22.3378
(95.60)
|
9.3582
(71.78)
|
31.6698
(84.08)
|
| GSK2487818; n=7, 18, 47, 56, 45, 28, 16, 3, 3 |
2.0320
(73.45)
|
3.2703
(143.75)
|
6.3474
(175.79)
|
8.0134
(146.43)
|
6.4276
(278.04)
|
9.6617
(207.18)
|
19.9693
(94.09)
|
8.4327
(64.98)
|
29.3042
(72.06)
|
| GSK2506102; n=8, 19, 51, 59, 45, 28, 16, 3, 3 |
0.8328
(101.92)
|
1.4018
(84.93)
|
2.0385
(85.59)
|
2.8357
(68.15)
|
3.2007
(89.86)
|
3.5712
(96.48)
|
6.4555
(59.57)
|
2.4981
(71.38)
|
7.1245
(87.62)
|
| GSK2506104; n=8, 19, 51, 59, 45, 28, 16, 3, 3 |
3.2020
(81.23)
|
5.2039
(98.70)
|
7.5220
(131.81)
|
10.8186
(84.31)
|
11.5783
(130.74)
|
13.8509
(125.27)
|
24.4926
(84.96)
|
9.5457
(73.58)
|
30.4034
(79.13)
|
| GSK2531398; n=8, 17, 46, 59, 45, 27, 16, 3, 3 |
1.2731
(57.92)
|
2.3676
(84.23)
|
3.7348
(131.10)
|
3.8017
(177.36)
|
4.0850
(209.29)
|
6.1029
(137.40)
|
10.7532
(98.46)
|
4.6296
(72.00)
|
14.7844
(81.18)
|
| GSK2531401; n=7, 19, 51, 59, 45, 28, 16, 3, 3 |
2.0473
(100.05)
|
4.0012
(88.64)
|
5.4631
(120.63)
|
8.8488
(80.17)
|
8.4814
(93.83)
|
10.7368
(90.83)
|
14.7926
(59.24)
|
7.1458
(174.98)
|
20.1044
(67.56)
|
Adverse Events
| Time Frame | Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406). | |||
| Arm/Group Title | Daprodustat | Epoetin Alfa | ||
| Arm/Group Description | Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose. | Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose. | ||
All Cause Mortality |
||||
| Daprodustat | Epoetin Alfa | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 18/270 (6.7%) | 10/136 (7.4%) | ||
Serious Adverse Events |
||||
| Daprodustat | Epoetin Alfa | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 80/270 (29.6%) | 47/136 (34.6%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 2/270 (0.7%) | 2 | 3/136 (2.2%) | 4 |
| Normocytic anaemia | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Cardiac disorders | ||||
| Angina unstable | 0/270 (0%) | 0 | 3/136 (2.2%) | 4 |
| Atrial fibrillation | 1/270 (0.4%) | 1 | 2/136 (1.5%) | 2 |
| Myocardial infarction | 3/270 (1.1%) | 3 | 0/136 (0%) | 0 |
| Acute coronary syndrome | 2/270 (0.7%) | 2 | 0/136 (0%) | 0 |
| Acute myocardial infarction | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 2 |
| Angina pectoris | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Cardiac failure | 2/270 (0.7%) | 2 | 0/136 (0%) | 0 |
| Atrioventricular block complete | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Cardiac arrest | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Cardiac failure congestive | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Cardiomyopathy | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Coronary artery disease | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Supraventricular tachycardia | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Congenital, familial and genetic disorders | ||||
| Congenital cystic kidney disease | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Ear and labyrinth disorders | ||||
| Vertigo positional | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Endocrine disorders | ||||
| Hyperparathyroidism | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Gastrointestinal disorders | ||||
| Gastritis | 1/270 (0.4%) | 1 | 2/136 (1.5%) | 2 |
| Constipation | 2/270 (0.7%) | 2 | 0/136 (0%) | 0 |
| Diarrhoea | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Nausea | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Vomiting | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Abdominal pain | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Abdominal pain upper | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Chronic gastritis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Diabetic gastroparesis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Gastric antral vascular ectasia | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Gastric dilatation | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Gastric ulcer haemorrhage | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Gastrointestinal haemorrhage | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Impaired gastric emptying | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Pancreatitis acute | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Pancreatitis relapsing | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Upper gastrointestinal haemorrhage | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| General disorders | ||||
| Pyrexia | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Asthenia | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Catheter site inflammation | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Device related thrombosis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| General physical health deterioration | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Non-cardiac chest pain | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Thirst | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Fatigue | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Hepatobiliary disorders | ||||
| Bile duct stone | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Cholecystitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Infections and infestations | ||||
| Pneumonia | 9/270 (3.3%) | 9 | 5/136 (3.7%) | 5 |
| Clostridium difficile colitis | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Arteriovenous fistula site infection | 2/270 (0.7%) | 2 | 0/136 (0%) | 0 |
| Gangrene | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Gastroenteritis | 2/270 (0.7%) | 3 | 0/136 (0%) | 0 |
| Sepsis | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Septic shock | 2/270 (0.7%) | 2 | 0/136 (0%) | 0 |
| Acinetobacter infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Atypical pneumonia | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Bacteraemia | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Bronchitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Campylobacter colitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Catheter bacteraemia | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Cellulitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Ear infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Endocarditis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Enteritis infectious | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Enterococcal bacteraemia | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Escherichia urinary tract infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| H1N1 influenza | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Infected skin ulcer | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Influenza | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Injection site cellulitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Laryngitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Localised infection | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Osteomyelitis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Pharyngitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Postoperative wound infection | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Prostatitis Escherichia coli | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Proteus infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Pseudomembranous colitis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Pyelonephritis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Respiratory syncytial virus infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Respiratory tract infection | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Skin bacterial infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Tubo-ovarian abscess | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Upper respiratory tract infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Urosepsis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Urinary tract infection | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||
| Arteriovenous fistula thrombosis | 7/270 (2.6%) | 9 | 3/136 (2.2%) | 4 |
| Head injury | 2/270 (0.7%) | 2 | 2/136 (1.5%) | 2 |
| Arteriovenous fistula site complication | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Fall | 1/270 (0.4%) | 1 | 2/136 (1.5%) | 2 |
| Vascular graft occlusion | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Arteriovenous fistula occlusion | 0/270 (0%) | 0 | 1/136 (0.7%) | 2 |
| Arteriovenous fistula site haematoma | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Arteriovenous fistula site haemorrhage | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Arteriovenous graft site stenosis | 0/270 (0%) | 0 | 1/136 (0.7%) | 2 |
| Arthropod bite | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Joint injury | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Multiple fractures | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Post procedural haematoma | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Rib fracture | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Sternal fracture | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Subdural haematoma | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Tibia fracture | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Vascular access complication | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Vascular access malfunction | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Vascular access site thrombosis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Vascular access site pseudoaneurysm | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Metabolism and nutrition disorders | ||||
| Fluid overload | 2/270 (0.7%) | 2 | 2/136 (1.5%) | 2 |
| Hyperkalaemia | 3/270 (1.1%) | 3 | 1/136 (0.7%) | 2 |
| Diabetic ketoacidosis | 2/270 (0.7%) | 5 | 0/136 (0%) | 0 |
| Hypoglycaemia | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Diabetes mellitus | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||
| Arthritis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Cervical spinal stenosis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Musculoskeletal chest pain | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Neuropathic arthropathy | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Pain in extremity | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Pathological fracture | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Lip and/or oral cavity cancer | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Oropharyngeal cancer | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Smooth muscle cell neoplasm | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Squamous cell carcinoma of lung | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Nervous system disorders | ||||
| Cerebrovascular accident | 4/270 (1.5%) | 6 | 0/136 (0%) | 0 |
| Transient ischaemic attack | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Diabetic hyperglycaemic coma | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Generalised tonic-clonic seizure | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Haemorrhagic stroke | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Headache | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Hypertensive encephalopathy | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Ischaemic stroke | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Loss of consciousness | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Lumbar radiculopathy | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Myoclonus | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Syncope | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Product Issues | ||||
| Thrombosis in device | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Psychiatric disorders | ||||
| Confusional state | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Renal and urinary disorders | ||||
| Haematuria | 0/270 (0%) | 0 | 2/136 (1.5%) | 2 |
| Calculus urethral | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Reproductive system and breast disorders | ||||
| Postmenopausal haemorrhage | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute respiratory failure | 3/270 (1.1%) | 3 | 1/136 (0.7%) | 1 |
| Dyspnoea | 1/270 (0.4%) | 1 | 3/136 (2.2%) | 3 |
| Chronic obstructive pulmonary disease | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Hypoxia | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Pulmonary embolism | 0/270 (0%) | 0 | 2/136 (1.5%) | 2 |
| Respiratory failure | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Asthma | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Epistaxis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Haemoptysis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Pulmonary hypertension | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Pulmonary oedema | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Skin and subcutaneous tissue disorders | ||||
| Diabetic foot | 0/270 (0%) | 0 | 2/136 (1.5%) | 2 |
| Erythema | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Skin ulcer | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Vascular disorders | ||||
| Hypertension | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Hypertensive crisis | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 1 |
| Hypotension | 1/270 (0.4%) | 1 | 2/136 (1.5%) | 2 |
| Peripheral ischaemia | 2/270 (0.7%) | 2 | 1/136 (0.7%) | 2 |
| Deep vein thrombosis | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Extremity necrosis | 2/270 (0.7%) | 2 | 0/136 (0%) | 0 |
| Haemorrhage | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Hypertensive emergency | 1/270 (0.4%) | 1 | 1/136 (0.7%) | 1 |
| Arterial occlusive disease | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Brachiocephalic vein stenosis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Dialysis induced hypertension | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Haematoma | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Ischaemia | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Malignant hypertension | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Orthostatic hypotension | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Peripheral vascular disorder | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
| Subclavian vein thrombosis | 1/270 (0.4%) | 1 | 0/136 (0%) | 0 |
| Thrombophlebitis | 0/270 (0%) | 0 | 1/136 (0.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Daprodustat | Epoetin Alfa | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 74/270 (27.4%) | 42/136 (30.9%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | 23/270 (8.5%) | 36 | 14/136 (10.3%) | 19 |
| Vomiting | 15/270 (5.6%) | 16 | 13/136 (9.6%) | 15 |
| Nausea | 6/270 (2.2%) | 8 | 11/136 (8.1%) | 21 |
| Abdominal pain | 7/270 (2.6%) | 8 | 9/136 (6.6%) | 9 |
| General disorders | ||||
| Pyrexia | 7/270 (2.6%) | 9 | 8/136 (5.9%) | 9 |
| Nervous system disorders | ||||
| Headache | 11/270 (4.1%) | 13 | 13/136 (9.6%) | 26 |
| Vascular disorders | ||||
| Hypertension | 22/270 (8.1%) | 35 | 14/136 (10.3%) | 19 |
| Hypotension | 12/270 (4.4%) | 16 | 9/136 (6.6%) | 13 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
| Name/Title | GSK Response Center |
|---|---|
| Organization | GlaxoSmithKline |
| Phone | 866-435-7343 |
| GSKClinicalSupportHD@gsk.com |
Responsible Party:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT03400033
Other Study ID Numbers:
- 204837
- 2017-004372-56
First Posted:
Jan 17, 2018
Last Update Posted:
Jul 12, 2021
Last Verified:
Jun 1, 2021