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

Anaemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03400033
• Other study ID #: 204837
• Secondary ID: 2017-004372-56
• Status: Completed
• Phase: Phase 3
• Start date: September 5, 2018
• Est. completion date: June 19, 2020

Study information

• Verified date: June 2021
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 407
• Est. completion date: June 19, 2020
• Est. primary completion date: June 19, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Anaemia
• Anemia
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

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

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Mar del Plata	Buenos Aires
Argentina	GSK Investigational Site	Pergamino	Buenos Aires
Argentina	GSK Investigational Site	Rosario	Santa Fe
Argentina	GSK Investigational Site	Sarandi	Buenos Aires
Australia	GSK Investigational Site	Heidelberg	Victoria
Australia	GSK Investigational Site	Parkville	Victoria
Brazil	GSK Investigational Site	Belo Horizonte, Minas Gerais
Brazil	GSK Investigational Site	Curitiba	Paraná
Brazil	GSK Investigational Site	Passo Fundo	Rio Grande Do Sul
Brazil	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul
Brazil	GSK Investigational Site	Salvador	Bahia
Brazil	GSK Investigational Site	Sao Jose do Rio Preto	São Paulo
Brazil	GSK Investigational Site	São Paulo
Canada	GSK Investigational Site	Oshawa	Ontario
France	GSK Investigational Site	Bayonne
France	GSK Investigational Site	Epagny Metz-Tessy
France	GSK Investigational Site	Le Mans
France	GSK Investigational Site	Nice Cedex 1
France	GSK Investigational Site	Strasbourg
Italy	GSK Investigational Site	Bologna	Emilia-Romagna
Italy	GSK Investigational Site	Modena	Emilia-Romagna
Italy	GSK Investigational Site	Pavia	Lombardia
Italy	GSK Investigational Site	Verona	Veneto
Korea, Republic of	GSK Investigational Site	Anyang-Si, Gyeonggi-do
Korea, Republic of	GSK Investigational Site	Busan
Korea, Republic of	GSK Investigational Site	Goyang-si, Gyeonggi-do
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Poland	GSK Investigational Site	Katowice
Poland	GSK Investigational Site	Lodz
Poland	GSK Investigational Site	Sandomierz
Poland	GSK Investigational Site	Tarnowskie Gory
Poland	GSK Investigational Site	Zyrardow
Romania	GSK Investigational Site	Constanta
Romania	GSK Investigational Site	Resita
Russian Federation	GSK Investigational Site	Kazan
Russian Federation	GSK Investigational Site	Kolomna
Russian Federation	GSK Investigational Site	Krasnodar
Russian Federation	GSK Investigational Site	Krasnogorsk
Russian Federation	GSK Investigational Site	Mytischi
Russian Federation	GSK Investigational Site	Novorossiysk
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Omsk
Russian Federation	GSK Investigational Site	Orenburg
Russian Federation	GSK Investigational Site	Penza
Russian Federation	GSK Investigational Site	Podolsk
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	St-Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	Ufa
Russian Federation	GSK Investigational Site	Yaroslavl
Spain	GSK Investigational Site	Almeria
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Gerona
Spain	GSK Investigational Site	Granollers, Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Manises (Valencia)
Spain	GSK Investigational Site	Sanlúcar De Barrameda (Cádiz)
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Sheffield
United Kingdom	GSK Investigational Site	Swansea
United States	GSK Investigational Site	Albuquerque	New Mexico
United States	GSK Investigational Site	Alexandria	Virginia
United States	GSK Investigational Site	College Point	New York
United States	GSK Investigational Site	Fresno	California
United States	GSK Investigational Site	Hampton	Virginia
United States	GSK Investigational Site	Hollywood	Florida
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Kansas City	Missouri
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Lufkin	Texas
United States	GSK Investigational Site	Macon	Georgia
United States	GSK Investigational Site	Meridian	Idaho
United States	GSK Investigational Site	Mesa	Arizona
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Middlebury	Connecticut
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Oklahoma City	Oklahoma
United States	GSK Investigational Site	Paramount	California
United States	GSK Investigational Site	Pittsfield	Massachusetts
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  France,  Italy,  Korea, Republic of,  Poland,  Romania,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline in Hemoglobin Levels Over the Evaluation Period (Week 28 to Week 52)	Blood samples were collected from participants for hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis, the missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputations. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region.	Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)
Secondary	Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant	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.	Day 1 to Week 52
Secondary	Change From Baseline in Hemoglobin Levels at 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.	Baseline (Pre-dose on Day 1) and Week 52
Secondary	Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (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.	Week 28 to Week 52
Secondary	Number of Hemoglobin Responders in the Hemoglobin Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (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.	Week 28 to Week 52
Secondary	Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria	Percentage of participants permanently stopping study treatment due to meeting rescue criteria has been presented.	Up to Week 52
Secondary	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at 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.	Baseline (Week -4 ) and Week 52
Secondary	Change From Baseline in SBP, DBP and MAP at End of Treatment	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.	Baseline (Week -4) and end of treatment (last on-treatment value until Week 52)
Secondary	Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years	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.	Up to 52 weeks
Secondary	Number of Participants With at Least One BP Exacerbation Event During the Study	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.	Up to 52 weeks
Secondary	Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S)	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.	Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52
Secondary	Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)	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).	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
Secondary	Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)	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).	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