Trial Outcomes & Findings for Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ) (NCT NCT03409107)

Last Updated: 2024-04-02

Results Overview

Blood samples were collected at given time points from participants for hemoglobin measurements. Evaluation period hemoglobin value was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 24 to Week 28 inclusive). For the primary analysis, the missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputations. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

614 participants

Primary outcome timeframe

Baseline (Day 1) and Week 24 to Week 28

Results posted on

2024-04-02

Participant Flow

This was a multicenter study conducted at 142 centers in 14 countries. Participants were randomized to receive either Daprodustat or Placebo.

A total of 1336 participants were screened, of which 722 were screen failures. A total of 614 participants were enrolled in the study.

Participant milestones

Participant milestones
Measure	Placebo Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Overall Study STARTED	307	307
Overall Study COMPLETED	290	300
Overall Study NOT COMPLETED	17	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Overall Study Withdrawal by Subject	4	2
Overall Study Physician Decision	1	0
Overall Study Lost to Follow-up	7	2
Overall Study Adverse Event	5	3

Baseline Characteristics

Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])	Total n=614 Participants Total of all reporting groups
Age, Continuous	66.6 Years STANDARD_DEVIATION 12.93 • n=5 Participants	65.3 Years STANDARD_DEVIATION 13.43 • n=7 Participants	65.9 Years STANDARD_DEVIATION 13.19 • n=5 Participants
Sex: Female, Male Female	178 Participants n=5 Participants	176 Participants n=7 Participants	354 Participants n=5 Participants
Sex: Female, Male Male	129 Participants n=5 Participants	131 Participants n=7 Participants	260 Participants n=5 Participants
Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE	34 Participants n=5 Participants	34 Participants n=7 Participants	68 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN: CENTRAL/SOUTH ASIAN HERITAGE	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN: JAPANESE/EASTASIAN/SOUTHEAST ASIAN HERITAGE	24 Participants n=5 Participants	24 Participants n=7 Participants	48 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN: MIXED ASIAN RACE	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN	47 Participants n=5 Participants	44 Participants n=7 Participants	91 Participants n=5 Participants
Race/Ethnicity, Customized NATIVE HAWAIIAN/OTHER PACIFIC ISLANDER	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized WHITE	195 Participants n=5 Participants	197 Participants n=7 Participants	392 Participants n=5 Participants
Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN AND WHITE	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day 1) and Week 24 to Week 28

Population: Intent-to-Treat (ITT) Population comprised all randomized participants regardless of whether they took study drug.

Outcome measures

Outcome measures
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Mean Change in Hemoglobin From Baseline and Over the Evaluation Period (Mean Over Week 24 and 28)	0.19 Grams per deciliter Standard Error 0.062	1.58 Grams per deciliter Standard Error 0.061

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 24 to Week 28

Population: Intent-to-Treat population.

Blood samples were collected at given time points for hemoglobin measurements. Evaluation period hemoglobin value was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 24 to Week 28 inclusive). 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. Percentage of participants with hemoglobin increase of \>=1.0 grams per deciliter from Baseline to evaluation period was analyzed using Cochran-Mantel-Haenszel (CMH) chi-squared test. The percentage values presented has been rounded off.

Outcome measures

Outcome measures
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Percentage of Participants With Hemoglobin Increase of >=1.0 Grams Per Deciliter From Baseline to Evaluation Period	18 Percentage of participants	77 Percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population.

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the 8 health domains: Physical Functioning, Role-Physical (role limitations caused by physical problems), Social Functioning, Bodily Pain, Mental Health, Role-Emotional (role limitations caused by emotional problems), Vitality, and General Perception of Health.Each domain is scored from 0 (poorer health) to 100 (better health). Vitality domain score ranges from 0-100; higher score indicates a better health state \& better functioning. Change from Baseline was calculated as Post-Dose Visit Value at Week 28 minus Baseline. For primary analysis, the missing on-treatment Week 28 SF-36 Vitality domain scores were imputed using pre-specified multiple imputations. Baseline value was latest non-missing pre-dose assessment on or before randomization date. Analysis was performed using ANCOVA model with terms for treatment, Baseline score, and region.

Outcome measures

Outcome measures
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in Short Form-36 (SF-36) Questionnaire Vitality Domain Score by Traditional Scoring at Week 28	1.93 Scores on a scale Standard Error 1.161	7.29 Scores on a scale Standard Error 1.121

SECONDARY outcome

Timeframe: Week 24 to Week 28

Population: Intent-to-Treat Population.

Mean hemoglobin during the evaluation period was defined as the mean of all evaluable hemoglobin values during the evaluation period (Week 24 to Week 28 inclusive) including any evaluable unscheduled hemoglobin values that were taken during this period. Percentage of participants with Hgb response was defined as participants with mean Hgb within range (11-12 grams per deciliter during the evaluation period (Week 24 to Week 28 inclusive) and it was analyzed using Cochran-Mantel-Haenszel (CMH) chi-squared test. The percentage values presented has been rounded off.

Outcome measures

Outcome measures
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Percentage of Participants With Hgb Response (Hgb in the 11-12 Grams/Deciliter Range) During Evaluation Period (Week 24 to Week 28 Inclusive)	8 Percentage of participants	52 Percentage of participants

SECONDARY outcome

Timeframe: Week 24 to Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

Percentage of days for which participant's Hgb was within the target range of 11-12 grams per deciliter during the evaluation period (Week 24 to Week 28 inclusive), including any unscheduled evaluable Hgb values that were taken during this time period. Percentage of time for which Hgb was within the target range (11-12 grams per deciliter) for a participant was calculated by dividing 'the total number of days that Hgb was within range during Week 24 to 28' by 'the total number of days the participant remained on treatment during Week 24 to 28'.

Outcome measures

Outcome measures
Measure	Placebo n=216 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=252 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Percentage of Time With Hgb Within the Target Range (11-12 Grams Per Deciliter) During Evaluation Period (Week 24 to Week 28 Inclusive) (Hodges-Lehmann Estimate)	0.00 Percentage of days Interval 0.0 to 100.0	53.59 Percentage of days Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: Week 24 to Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

Outcome measures

Outcome measures
Measure	Placebo n=216 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=252 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Percentage of Time With Hgb Within the Target Range (11-12 Grams Per Deciliter) During Evaluation Period (Week 24 to Week 28 Inclusive) (Mann-Whitney Estimate)	0.00 Percentage of days Interval 0.0 to 100.0	53.59 Percentage of days Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

Blood samples were collected at given time points for hemoglobin measurements. Change from Baseline in Hgb was analyzed using a mixed model repeated measures (MMRM) approach. Change from Baseline was calculated as Post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=301 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=299 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in Post-randomization Hgb at Week 28	0.20 Grams per deciliter Standard Error 0.070	1.56 Grams per deciliter Standard Error 0.069

SECONDARY outcome

Timeframe: Up to Week 28

Population: Intent-to-Treat Population.

The incidence rate of participants permanently stopping randomized treatment due to meeting rescue criteria is presented.

Outcome measures

Outcome measures
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Rate of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria	18.88 Events per 100 person year Interval 12.33 to 27.66	1.33 Events per 100 person year Interval 0.16 to 4.82

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

CKD-AQ is 21-item patient reported outcomes measure assessing symptoms \& symptom impact in participants with anemia associated with CKD.CKD-AQ identified 3 domains:1.Tired/Low Energy/Weak scale consisting of ten items;2.Chest Pain/Shortness of Breath scale consisting of four items and 3.Cognitive scale consisting of three items;Single items included: 4.Difficulty Sleeping;5.Difficulty Standing for long periods of time;6.Severity-Shortness of breath while sitting/resting;7.Time with Shortness of breath while not doing activity.Single-item measures were recorded based on 0-100 scoring with 0 is worst possible \& 100 is best possible score.Total domain score is calculated as average of items in each domain \& ranged from 0-100 where 0 is worst possible and 100 is best possible score.Change from Baseline was calculated as post-dose visit value minus Baseline.Baseline was latest non-missing pre-dose assessment on or before randomization date. Adjusted mean \& standard error is presented.

Outcome measures

Outcome measures
Measure	Placebo n=193 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=212 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Tired/Low Energy/Weak Domain	2.81 Scores on a scale Standard Error 1.132	8.72 Scores on a scale Standard Error 1.086
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Chest Pain/Shortness of Breath Domain	0.62 Scores on a scale Standard Error 0.971	3.55 Scores on a scale Standard Error 0.932
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Cognitive Domain	0.48 Scores on a scale Standard Error 1.042	4.27 Scores on a scale Standard Error 0.999
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Difficulty in Sleeping	2.61 Scores on a scale Standard Error 1.643	5.22 Scores on a scale Standard Error 1.577
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Difficulty Standing for Long Periods of Time	1.55 Scores on a scale Standard Error 1.630	6.19 Scores on a scale Standard Error 1.563
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Severity-Shortness of Breath, Sitting/Resting	0.43 Scores on a scale Standard Error 0.995	3.11 Scores on a scale Standard Error 0.954
Change From Baseline by Domain and Single Item Scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) Symptom Questionnaire Time with Shortness of BreathnotDoingActivity	0.29 Scores on a scale Standard Error 1.083	2.30 Scores on a scale Standard Error 1.037

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

The PGI-S is a 1-item questionnaire designed to assess participant's impression of disease severity on a 5-point disease severity scale (0=absent, 1=mild, 2=moderate, 3=severe, or 4=very severe). A higher score indicated worse outcome. Change from Baseline was calculated as Post-Dose visit value minus Baseline value. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Adjusted mean and standard error is presented.

Outcome measures

Outcome measures
Measure	Placebo n=193 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=212 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in Patient Global Impression of Severity (PGI-S)	-0.04 Scores on a scale Standard Error 0.055	-0.18 Scores on a scale Standard Error 0.052

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following eight health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality, and general perception of health. Each domain is scored from 0 (poorer health) to 100 (better health). Physical functioning domain score ranges from 0-100; higher score indicates a better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=190 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=210 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in the SF-36 Physical Functioning Domain	1.23 Scores on a scale Standard Error 1.354	3.80 Scores on a scale Standard Error 1.298

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following eight health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality, and general perception of health. Individual vitality items include: 1. Did you feel full of life?, 2. Did you have a lot of energy?, 3. Did you feel worn out?, 4. Did you feel tired?. Score of each item in the vitality domain ranges from 0-100; higher score indicates better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=190 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=210 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline of the SF-36 Individual Items in the Vitality Domain Did you feel full of life?	-0.02 Scores on a scale Standard Error 0.070	0.16 Scores on a scale Standard Error 0.067
Change From Baseline of the SF-36 Individual Items in the Vitality Domain Did you have a lot of energy?	0.09 Scores on a scale Standard Error 0.066	0.26 Scores on a scale Standard Error 0.063
Change From Baseline of the SF-36 Individual Items in the Vitality Domain Did you feel worn out?	0.16 Scores on a scale Standard Error 0.067	0.34 Scores on a scale Standard Error 0.064
Change From Baseline of the SF-36 Individual Items in the Vitality Domain Did you feel tired?	0.08 Scores on a scale Standard Error 0.060	0.34 Scores on a scale Standard Error 0.057

SECONDARY outcome

Timeframe: Week 8, Week 12 and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).

WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities. It contains 2 concepts-work productivity impairment measured via absenteeism(time missed from work), presenteeism(impairment at work) and regular daily activity impairment. WPAI questions (Q) were:1) currently employed,2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. WPAI generates 4 domain scores:percent (%) of work time missed(absenteeism),% of impairment while working(presenteeism),% of overall work impairment(absenteeism and presenteeism combined),% of activity impairment. Number of participants currently employed as per WPAI-ANS-CPV is presented.

Outcome measures

Outcome measures
Measure	Placebo n=249 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=251 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV) Week 8, No, n=249, 250	195 Participants	204 Participants
Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV) Week 8, Yes, n=249, 250	54 Participants	46 Participants
Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV) Week 12, No, n=234, 251	183 Participants	212 Participants
Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV) Week 12, Yes, n=234, 251	51 Participants	39 Participants
Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV) Week 28, No, n=193, 213	158 Participants	178 Participants
Number of Participants Currently Employed as Per Work Productivity and Activity Impairment Questionnaire: Anemic Symptoms Clinical Practice Version (WPAI-ANS-CPV) Week 28, Yes, n=193, 213	35 Participants	35 Participants

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 8, Week 12 and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).

WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities. It contains 2 concepts-work productivity impairment measured via absenteeism (time missed from work), presenteeism (impairment at work) and regular daily activity impairment. WPAI questions (Q) were: 1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4)overall work impairment due to problem, 5) activity impairment due to problem. Percent work time missed due to problem was a subscale and calculated as: Q2/(Q2+Q4) for those who were currently employed. Subscale score was expressed as an impairment percentage (range: 0-100%) where higher numbers indicate greater impairment and less productivity. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=50 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=39 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in WPAI-ANS-CPV: Percent Time Missed From Work Week 8, n=50, 39	-2.4 Percentage of time Standard Deviation 28.40	-6.1 Percentage of time Standard Deviation 24.92
Change From Baseline in WPAI-ANS-CPV: Percent Time Missed From Work Week 12, n=46, 31	0.9 Percentage of time Standard Deviation 28.79	4.2 Percentage of time Standard Deviation 27.96
Change From Baseline in WPAI-ANS-CPV: Percent Time Missed From Work Week 28, n=28, 25	0.0 Percentage of time Standard Deviation 33.59	0.3 Percentage of time Standard Deviation 31.01

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 8, Week 12 and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at indicated time points are presented (presented by n=X in category titles).

WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities. It contains 2 concepts-work productivity impairment measured via absenteeism (time missed from work), presenteeism (impairment at work) and regular daily activity impairment. WPAI Qs were: 1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=50 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=39 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in WPAI-ANS-CPV: Mean Hours Missed From Work in the Past 7 Days Week 8, n=50, 39	0.1 Percentage of hours Standard Deviation 18.46	-1.8 Percentage of hours Standard Deviation 11.88
Change From Baseline in WPAI-ANS-CPV: Mean Hours Missed From Work in the Past 7 Days Week 12, n=46, 31	1.4 Percentage of hours Standard Deviation 14.07	2.4 Percentage of hours Standard Deviation 16.83
Change From Baseline in WPAI-ANS-CPV: Mean Hours Missed From Work in the Past 7 Days Week 28, n=28, 25	0.3 Percentage of hours Standard Deviation 19.90	1.0 Percentage of hours Standard Deviation 14.24

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 8, Week 12 and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).

WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities.It contains 2 concepts-work productivity impairment measured via absenteeism(time missed from work),presenteeism(impairment at work) and regular daily activity impairment.WPAI Qs were:1)currently employed,2)work time missed due to problem,3)impairment while working due to problem,4)overall work impairment due to problem,5)activity impairment due to problem. % Impairment while Working due to Problem was subscale and calculated as: Q5/10 for those who were currently employed and actually worked in past 7 days. Subscale score was expressed as an impairment percentage (range: 0-100%) where higher numbers indicate greater impairment and less productivity. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=45 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=32 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in WPAI: Percent Impairment at Work Week 8, n=45, 32	-5.1 Percentage of impairment Standard Deviation 18.42	-11.3 Percentage of impairment Standard Deviation 24.06
Change From Baseline in WPAI: Percent Impairment at Work Week 12, n=41, 26	-4.6 Percentage of impairment Standard Deviation 18.99	-8.8 Percentage of impairment Standard Deviation 23.38
Change From Baseline in WPAI: Percent Impairment at Work Week 28, n=24, 20	-9.6 Percentage of impairment Standard Deviation 25.62	-9.0 Percentage of impairment Standard Deviation 22.92

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 8, Week 12 and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).

WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities. It contains 2 concepts-work productivity impairment measured via absenteeism (time missed from work), presenteeism (impairment at work) and regular daily activity impairment. WPAI Qs were: 1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. Percent overall work impairment due to problem was a subscale and calculated as: Q2/(Q2+Q4)+\[(1-Q2/(Q2+Q4))×(Q5/10)\] for those who were currently employed. Subscale score was expressed as an impairment percentage (range: 0-100%) where higher numbers indicate greater impairment. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=45 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=32 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in WPAI: Percent Overall Work Impairment Week 8, n=45, 32	-4.3 Percentage of impairment Standard Deviation 24.04	-12.0 Percentage of impairment Standard Deviation 25.90
Change From Baseline in WPAI: Percent Overall Work Impairment Week 12, n=41, 26	0.5 Percentage of impairment Standard Deviation 25.81	-3.2 Percentage of impairment Standard Deviation 33.35
Change From Baseline in WPAI: Percent Overall Work Impairment Week 28, n=24, 20	-9.3 Percentage of impairment Standard Deviation 37.45	-8.4 Percentage of impairment Standard Deviation 19.12

SECONDARY outcome

Timeframe: Baseline (Day 1), Week 8, Week 12 and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).

WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities.It contains 2 concepts-work productivity impairment measured via absenteeism (time missed from work), presenteeism (impairment at work) and regular daily activity impairment. WPAI Qs were: 1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. Percent activity impairment due to problem was a subscale and calculated as: Q5/10 for all respondents. Subscale score was expressed as an impairment percentage (range: 0-100%) where higher numbers indicate greater impairment. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=246 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=248 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in WPAI: Percent Regular Daily Activity Impairment Week 8, n=243, 248	-4.6 Percentage of impairment Standard Deviation 23.67	-7.7 Percentage of impairment Standard Deviation 24.53
Change From Baseline in WPAI: Percent Regular Daily Activity Impairment Week 12, n=228, 246	-5.2 Percentage of impairment Standard Deviation 25.40	-8.6 Percentage of impairment Standard Deviation 24.58
Change From Baseline in WPAI: Percent Regular Daily Activity Impairment Week 28, n=187, 210	-6.7 Percentage of impairment Standard Deviation 28.93	-12.2 Percentage of impairment Standard Deviation 27.50

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at indicated time points are presented.

The EQ-5D-5L is a self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a 5-point Likert scale (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, and 5: extreme problems). The responses for the five dimension together form a five-figure description of health state. Each of these five-figure health states have attached valuation (utility score), expressed as single index on a scale from 0-1, where 1 is full health and 0 is worst health. The higher the score the better the health status. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=106 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=116 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) Utility Score	0.01 Scores on a scale Standard Error 0.015	0.03 Scores on a scale Standard Error 0.014

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labeled 'the best health you can imagine' and 'the worst health you can imagine' at the time of completion. It is a self-assessment visual analogue scale, ranging from 0=worst imaginable to 100=best. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=106 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=116 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in EuroQol Visual Analogue Scale (EQ-VAS) Score	0.80 Scores on a scale Standard Error 1.427	5.30 Scores on a scale Standard Error 1.373

SECONDARY outcome

Timeframe: Baseline (Day 1) and Week 28

Population: Intent-to-Treat Population. Only those participants with data available at the indicated time points were analyzed.

SBP, DBP and MAP were measured with participants in a seated position after at least a 5-minute of rest. MAP is the average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Placebo n=202 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=230 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Pressure (MAP) at Week 28 SBP	-0.63 Millimeters of mercury (mmHg) Standard Error 1.045	-0.23 Millimeters of mercury (mmHg) Standard Error 0.981
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Pressure (MAP) at Week 28 DBP	-0.96 Millimeters of mercury (mmHg) Standard Error 0.625	0.84 Millimeters of mercury (mmHg) Standard Error 0.587
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Pressure (MAP) at Week 28 MAP	-0.82 Millimeters of mercury (mmHg) Standard Error 0.674	0.49 Millimeters of mercury (mmHg) Standard Error 0.632

SECONDARY outcome

Timeframe: Up to Week 28

Population: Intent-to-Treat Population.

Percentage of participants with at least one BP event is presented. BP exacerbation is defined as: SBP exacerbation: SBP \>= 25 mmHg increase from Baseline or SBP \>= 180 mmHg; DBP exacerbation: DBP \>= 15 mmHg increase from Baseline or DBP \>= 110 mmHg. Percentage of participants with at least one BP event is presented. The percentage values presented has been rounded off.

Outcome measures

Outcome measures
Measure	Placebo n=307 Participants Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=307 Participants Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Percentage of Participants With at Least One Blood Pressure (BP) Exacerbation Event	26 Percentage of participants	32 Percentage of participants

Adverse Events

Placebo

Serious events: 68 serious events

Other events: 44 other events

Deaths: 16 deaths

Daprodustat

Serious events: 62 serious events

Other events: 49 other events

Deaths: 10 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=306 participants at risk Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.	Daprodustat n=308 participants at risk Participants received daprodustat tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter \[g/dL\])
Gastrointestinal disorders Diarrhoea	5.6% 17/306 • Number of events 22 • All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32). Safety Population comprised of all randomized participants who received at least 1 dose of study treatment. Treatment emergent non-serious adverse events and serious adverse events are reported. One participant who was randomized to placebo accidently received daprodustat during the study and therefore was evaluated in the daprodustat treatment group for the safety outcomes	7.8% 24/308 • Number of events 26 • All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32). Safety Population comprised of all randomized participants who received at least 1 dose of study treatment. Treatment emergent non-serious adverse events and serious adverse events are reported. One participant who was randomized to placebo accidently received daprodustat during the study and therefore was evaluated in the daprodustat treatment group for the safety outcomes
Vascular disorders Hypertension	4.6% 14/306 • Number of events 14 • All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32). Safety Population comprised of all randomized participants who received at least 1 dose of study treatment. Treatment emergent non-serious adverse events and serious adverse events are reported. One participant who was randomized to placebo accidently received daprodustat during the study and therefore was evaluated in the daprodustat treatment group for the safety outcomes	6.8% 21/308 • Number of events 27 • All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32). Safety Population comprised of all randomized participants who received at least 1 dose of study treatment. Treatment emergent non-serious adverse events and serious adverse events are reported. One participant who was randomized to placebo accidently received daprodustat during the study and therefore was evaluated in the daprodustat treatment group for the safety outcomes
General disorders Oedema peripheral	6.9% 21/306 • Number of events 23 • All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32). Safety Population comprised of all randomized participants who received at least 1 dose of study treatment. Treatment emergent non-serious adverse events and serious adverse events are reported. One participant who was randomized to placebo accidently received daprodustat during the study and therefore was evaluated in the daprodustat treatment group for the safety outcomes	3.9% 12/308 • Number of events 14 • All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32). Safety Population comprised of all randomized participants who received at least 1 dose of study treatment. Treatment emergent non-serious adverse events and serious adverse events are reported. One participant who was randomized to placebo accidently received daprodustat during the study and therefore was evaluated in the daprodustat treatment group for the safety outcomes

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee 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
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