Anemia, Dialysis Dependent Chronic Kidney Disease
Conditions
Keywords
Anemia, kidney, dialysis dependent chronic kidney disease, CKD, DD, renal, vadadustat, AKB-6548, hypoxia-inducible factor, Akebia (AKB), hypoxia-inducible factor (HIF), HIF, prolyl-hydroxylase inhibitor (PHI), PHI, Japan, Japanese
Brief summary
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding study to assess the efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of orally administered vadadustat in Japanese participants with anemia secondary to Dialysis-dependent Chronic Kidney Disease (DD-CKD).
Interventions
DRUGVadadustat
Daily oral dose
DRUGPlacebo
Daily oral dose
Sponsors
Akebia Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female Japanese participants ≥20 years of age * Receiving chronic maintenance hemodialysis for end-stage kidney disease * Hemoglobin (Hb) \<10.0 grams per deciliter (g/dL)
Exclusion criteria
* Anemia due to a cause other than chronic kidney disease (CKD) or presence of active bleeding or recent blood loss * Sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia * Red blood cell transfusion within 4 weeks prior to or during screening * Anticipated to recover adequate kidney function to no longer require hemodialysis during study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period | Pre-treatment; Week 6 | The pre-treatment average value for Hb was defined as the average of 3 values obtained prior to treatment, i.e., the qualifying screening value and the Baseline value. Change from Pre-treatment was calculated as the Week 6 value minus the Pre-treatment value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Hb Levels at the End of the Primary Efficacy Period | up to Week 6 | Data are reported as mean of the actual Week 6 values. |
| Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | up to Week 16 | Data are reported as mean of the actual Week 16 values. |
| Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | up to Week 16 | — |
| Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | Pre-treatment; Week 16 | A pre-treatment average value for Hb was defined as the average of 3 values obtained prior to dosing, i.e., the 2 qualifying screening values and the Baseline value. Change from Pre-treatment was calculated as the Week 16 value minus the Pre-treatment value. |
| Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | from Baseline up to Week 16 | Time for this analysis was measured from Day 1 (Baseline) through the point in time during either the Primary Efficacy Period or the Dose Adjustment and Maintenance Period when a participant's Hb level achieved the target range of 10.0 to 12.0 g/dL. |
| Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
| Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | Participants who initiated rescue therapy (including RBC transfusion) were required to stop study drug treatment and were discontinued from the study. |
| Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | Participants who initiated rescue therapy (including RBC transfusion) were required to stop study drug treatment and were discontinued from the study. |
| Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period | Baseline; Week 6 | ESA rescue is defined as participants with ESA administration and 1) the participant experienced a clinically significant worsening of their anemia or symptoms of anemia, 2) the participant's Hb level is \<9.0 g/dL, and 3) reason for early study withdrawal of worsening of anemia requiring ESA rescue or blood transfusion. Participants who initiated rescue therapy (including ESAs) were required to stop study drug treatment and were discontinued from the study. |
| Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | ESA rescue is defined as participants with ESA administration and 1) the participant experienced a clinically significant worsening of their anemia or symptoms of anemia, 2) the participant's Hb level is \<9.0 g/dL, and 3) reason for early study withdrawal of worsening of anemia requiring ESA rescue or blood transfusion. Participants who initiated rescue therapy (including ESAs) were required to stop study drug treatment and were discontinued from the study. |
| Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | up to Week 16 | Increases in dose were not allowed during the 6-week Primary Efficacy Period. |
| Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Week 4, pre-dose | Blood samples were collected for analysis. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | up to Week 6 | An adverse event (AE) was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. An AE that met one or more of the following criteria or outcomes was classified as serious: death; life-threatening; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; was considered a medically important event not meeting the above criteria, but which could jeopardize a participant, or could require medical or surgical intervention to prevent one of the criteria listed in this definition. |
| Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | up to Week 16 | An AE was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. An AE that met one or more of the following criteria or outcomes was classified as serious: death; life-threatening; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; was considered a medically important event not meeting the above criteria, but which could jeopardize a participant, or could require medical or surgical intervention to prevent one of the criteria listed in this definition. |
| Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | Baseline; Week 16 | Change from Baseline was calculated as the post-Baseline value minus the Baseline value. |
Countries
Japan
Participant flow
Pre-assignment details
Participants who had not recently received erythropoiesis-stimulating agent (ESA) therapy participated in 2 screening visits (SVs). Participants who had recently received ESA therapy and otherwise met the eligibility criteria were required to washout from ESA therapy prior to evaluation of screening hemoglobin levels and participate in 3 SVs.
Participants by arm
| Arm | Count |
|---|---|
| Vadadustat 150 mg Participants were randomized to receive vadadustat 150 milligrams (mg), administered as 1 tablet once daily (QD), for 6 weeks during the Primary Efficacy Period. During the 10-week Dose Adjustment and Maintenance Period, the dose was adjusted to achieve a target hemoglobin (Hb) of 10.0 to 12.0 grams/deciliter (g/dL) based on dose adjustment guidelines. | 15 |
| Vadadustat 300 mg Participants were randomized to receive vadadustat 300 mg, administered as 2 tablets QD, for 6 weeks during the Primary Efficacy Period. During the 10-week Dose Adjustment and Maintenance Period, the dose was adjusted to achieve a target Hb of 10.0 to 12.0 g/dL based on dose adjustment guidelines. | 15 |
| Vadadustat 600 mg Participants were randomized to receive vadadustat 600 mg, administered as 4 tablets QD, for 6 weeks during the Primary Efficacy Period. During the 10-week Dose Adjustment and Maintenance Period, the dose was adjusted to achieve a target Hb of 10.0 to 12.0 g/dL based on dose adjustment guidelines. | 15 |
| Placebo to Vadadustat 150 mg Participants were randomized to receive matching placebo for 6 weeks during the Primary Efficacy Period. During the 10-week Dose Adjustment and Maintenance Period, participants randomized to receive placebo in the 6-week Efficacy Period were switched to vadadustat 150 mg, and the dose was adjusted to achieve a target Hb of 10.0 to 12.0 g/dL based on dose adjustment guidelines. | 5 |
| Placebo to Vadadustat 300 mg Participants were randomized to receive matching placebo for 6 weeks during the Primary Efficacy Period. During the 10-week Dose Adjustment and Maintenance Period, participants randomized to receive placebo in the 6-week Efficacy Period were switched to vadadustat 300 mg, and the dose was adjusted to achieve a target Hb of 10.0 to 12.0 g/dL based on dose adjustment guidelines. | 5 |
| Placebo to Vadadustat 600 mg Participants were randomized to receive matching placebo for 6 weeks during the Primary Efficacy Period. During the 10-week Dose Adjustment and Maintenance Period, participants randomized to receive placebo in the 6-week Efficacy Period were switched to vadadustat 600 mg, and the dose was adjusted to achieve a target Hb of 10.0 to 12.0 g/dL based on dose adjustment guidelines. | 5 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Dose Adjustment and Maintenance Period | Captured as Other | 0 | 0 | 1 | 0 | 0 | 0 |
| Dose Adjustment and Maintenance Period | ESA Rescue/Blood Transfusion for Anemia | 1 | 0 | 0 | 1 | 0 | 0 |
| Primary Efficacy Period (6 Weeks) | ESA Rescue/Blood Transfusion for Anemia | 4 | 2 | 1 | 2 | 4 | 3 |
| Primary Efficacy Period (6 Weeks) | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Vadadustat 150 mg | Vadadustat 300 mg | Vadadustat 600 mg | Placebo to Vadadustat 150 mg | Placebo to Vadadustat 300 mg | Placebo to Vadadustat 600 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 11.01 | 64.3 years STANDARD_DEVIATION 8.02 | 65.1 years STANDARD_DEVIATION 9.05 | 60.8 years STANDARD_DEVIATION 12.85 | 61.0 years STANDARD_DEVIATION 15.6 | 70.8 years STANDARD_DEVIATION 8.23 | 63.8 years STANDARD_DEVIATION 10.16 |
| Hemoglobin Levels | 8.996 grams per deciliter (g/dL) STANDARD_DEVIATION 0.5229 | 8.793 grams per deciliter (g/dL) STANDARD_DEVIATION 0.5254 | 9.317 grams per deciliter (g/dL) STANDARD_DEVIATION 0.6222 | 8.827 grams per deciliter (g/dL) STANDARD_DEVIATION 0.6405 | 8.950 grams per deciliter (g/dL) STANDARD_DEVIATION 0.7331 | 9.133 grams per deciliter (g/dL) STANDARD_DEVIATION 0.6737 | 9.015 grams per deciliter (g/dL) STANDARD_DEVIATION 0.5935 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | 0 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 5 Participants | 2 Participants | 3 Participants | 2 Participants | 19 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 10 Participants | 3 Participants | 2 Participants | 3 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 15 | 11 / 15 | 6 / 15 | 2 / 5 | 2 / 5 | 2 / 5 | 9 / 15 | 9 / 15 | 9 / 15 | 1 / 5 | 1 / 5 | 2 / 5 |
| other Total, other adverse events | 8 / 15 | 11 / 15 | 5 / 15 | 2 / 5 | 2 / 5 | 2 / 5 | 9 / 15 | 9 / 15 | 9 / 15 | 1 / 5 | 1 / 5 | 2 / 5 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 3 / 15 | 0 / 5 | 1 / 5 | 0 / 5 | 1 / 15 | 1 / 15 | 1 / 15 | 0 / 5 | 0 / 5 | 0 / 5 |
Outcome results
Primary
Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period
The pre-treatment average value for Hb was defined as the average of 3 values obtained prior to treatment, i.e., the qualifying screening value and the Baseline value. Change from Pre-treatment was calculated as the Week 6 value minus the Pre-treatment value.
Time frame: Pre-treatment; Week 6
Population: Modified Intent-to-Treat Population (mITT): all randomized participants who received at least 1 dose of study medication, had a pre-treatment Hb average, and at least one post-Baseline Hb measurement. The mITT Population was based on the treatment to which participants were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period | -0.28 grams per deciliter (g/dL) | Standard Error 0.218 |
| Vadadustat 300 mg | Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period | 0.08 grams per deciliter (g/dL) | Standard Error 0.222 |
| Vadadustat 600 mg | Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period | 0.41 grams per deciliter (g/dL) | Standard Error 0.233 |
| Placebo | Mean Change in Hemoglobin (Hb) Levels From Pre-treatment to the End of the Primary Efficacy Period | -1.48 grams per deciliter (g/dL) | Standard Error 0.226 |
p-value: 0.000495% CI: [0.56, 1.82]ANCOVA
p-value: <0.000195% CI: [0.93, 2.19]ANCOVA
p-value: <0.000195% CI: [1.23, 2.54]ANCOVA
Secondary
Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Ferritin | -105.09 ng/mL | Standard Deviation 55.837 |
| Vadadustat 150 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Hepcidin | -73.826 ng/mL | Standard Deviation 50.9042 |
| Vadadustat 300 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Ferritin | -119.28 ng/mL | Standard Deviation 84 |
| Vadadustat 300 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Hepcidin | -99.367 ng/mL | Standard Deviation 51.3174 |
| Vadadustat 600 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Ferritin | -113.52 ng/mL | Standard Deviation 54.559 |
| Vadadustat 600 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Hepcidin | -106.838 ng/mL | Standard Deviation 40.1472 |
| Placebo | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Ferritin | -43.05 ng/mL | Standard Deviation 81.954 |
| Placebo | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Hepcidin | -95.940 ng/mL | Standard Deviation 98.7262 |
| Placebo to Vadadustat 300 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Ferritin | -150.70 ng/mL | — |
| Placebo to Vadadustat 300 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Hepcidin | -122.300 ng/mL | — |
| Placebo to Vadadustat 600 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Ferritin | -76.95 ng/mL | Standard Deviation 42.356 |
| Placebo to Vadadustat 600 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Dose Adjustment and Maintenance Period | Hepcidin | -35.140 ng/mL | Standard Deviation 62.9184 |
Secondary
Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Ferritin | -51.20 nanograms per milliliter (ng/mL) | Standard Deviation 58.855 |
| Vadadustat 150 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Hepcidin | -53.465 nanograms per milliliter (ng/mL) | Standard Deviation 43.5531 |
| Vadadustat 300 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Hepcidin | -73.587 nanograms per milliliter (ng/mL) | Standard Deviation 32.3547 |
| Vadadustat 300 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Ferritin | -68.67 nanograms per milliliter (ng/mL) | Standard Deviation 54.707 |
| Vadadustat 600 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Ferritin | -104.49 nanograms per milliliter (ng/mL) | Standard Deviation 49.558 |
| Vadadustat 600 mg | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Hepcidin | -104.301 nanograms per milliliter (ng/mL) | Standard Deviation 36.7636 |
| Placebo | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Ferritin | 12.63 nanograms per milliliter (ng/mL) | Standard Deviation 32.424 |
| Placebo | Mean Change in Ferritin and Hepcidin From Baseline to the End of the Primary Efficacy Period | Hepcidin | -11.802 nanograms per milliliter (ng/mL) | Standard Deviation 13.6518 |
Comparison: Ferritinp-value: 0.0207ANCOVA
Comparison: Ferritinp-value: 0.0022ANCOVA
Comparison: Ferritinp-value: <0.0001ANCOVA
Comparison: Hepcidinp-value: 0.0062ANCOVA
Comparison: Hepcidinp-value: 0.0002ANCOVA
Comparison: Hepcidinp-value: <0.0001ANCOVA
Secondary
Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period
A pre-treatment average value for Hb was defined as the average of 3 values obtained prior to dosing, i.e., the 2 qualifying screening values and the Baseline value. Change from Pre-treatment was calculated as the Week 16 value minus the Pre-treatment value.
Time frame: Pre-treatment; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | 1.397 g/dL | Standard Deviation 0.5755 |
| Vadadustat 300 mg | Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | 2.444 g/dL | Standard Deviation 1.7807 |
| Vadadustat 600 mg | Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | 1.644 g/dL | Standard Deviation 1.4973 |
| Placebo | Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | -0.233 g/dL | Standard Deviation 0.1414 |
| Placebo to Vadadustat 300 mg | Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | 3.800 g/dL | — |
| Placebo to Vadadustat 600 mg | Mean Change in Hb Between Pre-treatment and the End of the Dose Adjustment and Maintenance Period | 3.000 g/dL | Standard Deviation 0.2828 |
Secondary
Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Hematocrit | 5.12 percentage | Standard Deviation 2.105 |
| Vadadustat 150 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Reticulocytes | 0.32 percentage | Standard Deviation 0.636 |
| Vadadustat 300 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Hematocrit | 8.92 percentage | Standard Deviation 5.1 |
| Vadadustat 300 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Reticulocytes | 0.33 percentage | Standard Deviation 0.686 |
| Vadadustat 600 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Hematocrit | 5.63 percentage | Standard Deviation 4.921 |
| Vadadustat 600 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Reticulocytes | 0.24 percentage | Standard Deviation 0.547 |
| Placebo | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Hematocrit | 1.20 percentage | Standard Deviation 0 |
| Placebo | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Reticulocytes | 0.55 percentage | Standard Deviation 0.212 |
| Placebo to Vadadustat 300 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Hematocrit | 12.90 percentage | — |
| Placebo to Vadadustat 300 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Reticulocytes | 0.40 percentage | — |
| Placebo to Vadadustat 600 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Hematocrit | 10.70 percentage | Standard Deviation 1.697 |
| Placebo to Vadadustat 600 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Dose Adjustment and Maintenance Period | Reticulocytes | 0.15 percentage | Standard Deviation 0.636 |
Secondary
Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Hematocrit | 0.67 percentage | Standard Error 0.77 |
| Vadadustat 150 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Reticulocytes | 0.64 percentage | Standard Error 0.158 |
| Vadadustat 300 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Reticulocytes | 0.57 percentage | Standard Error 0.141 |
| Vadadustat 300 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Hematocrit | 1.98 percentage | Standard Error 0.737 |
| Vadadustat 600 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Hematocrit | 3.30 percentage | Standard Error 0.737 |
| Vadadustat 600 mg | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Reticulocytes | 0.71 percentage | Standard Error 0.14 |
| Placebo | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Hematocrit | -2.63 percentage | Standard Error 1.045 |
| Placebo | Mean Change in Hematocrit and Reticulocytes From Baseline to the End of the Primary Efficacy Period | Reticulocytes | 0.39 percentage | Standard Error 0.212 |
Comparison: Hematocritp-value: 0.015495% CI: [0.67, 5.94]ANCOVA
Comparison: Hematocritp-value: 0.000895% CI: [2.06, 7.16]ANCOVA
Comparison: Hematocritp-value: <0.000195% CI: [3.31, 8.56]ANCOVA
Comparison: Reticulocytesp-value: 0.357295% CI: [-0.3, 0.81]ANCOVA
Comparison: Reticulocytesp-value: 0.475895% CI: [-0.33, 0.69]ANCOVA
Comparison: Reticulocytesp-value: 0.204895% CI: [-0.19, 0.84]ANCOVA
Secondary
Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Iron | -18.5 μg/dL | Standard Deviation 24.01 |
| Vadadustat 150 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | TIBC | 58.5 μg/dL | Standard Deviation 44.12 |
| Vadadustat 300 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Iron | -8.7 μg/dL | Standard Deviation 24.29 |
| Vadadustat 300 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | TIBC | 80.9 μg/dL | Standard Deviation 29.42 |
| Vadadustat 600 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Iron | 0.9 μg/dL | Standard Deviation 48.22 |
| Vadadustat 600 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | TIBC | 85.4 μg/dL | Standard Deviation 39.91 |
| Placebo | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Iron | -9.5 μg/dL | Standard Deviation 30.41 |
| Placebo | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | TIBC | 33.0 μg/dL | Standard Deviation 2.83 |
| Placebo to Vadadustat 300 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Iron | -7.0 μg/dL | — |
| Placebo to Vadadustat 300 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | TIBC | 108.0 μg/dL | — |
| Placebo to Vadadustat 600 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | Iron | 15.0 μg/dL | Standard Deviation 43.84 |
| Placebo to Vadadustat 600 mg | Mean Change in Iron and TIBC From Baseline to the End of the Dose Adjustment and Maintenance Period | TIBC | 78.0 μg/dL | Standard Deviation 62.23 |
Secondary
Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | Iron | -3.3 micrograms per deciliter (μg/dL) | Standard Deviation 26.6 |
| Vadadustat 150 mg | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | TIBC | 35.4 micrograms per deciliter (μg/dL) | Standard Deviation 28.72 |
| Vadadustat 300 mg | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | TIBC | 67.5 micrograms per deciliter (μg/dL) | Standard Deviation 25.72 |
| Vadadustat 300 mg | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | Iron | -1.5 micrograms per deciliter (μg/dL) | Standard Deviation 19.5 |
| Vadadustat 600 mg | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | Iron | -8.1 micrograms per deciliter (μg/dL) | Standard Deviation 21.95 |
| Vadadustat 600 mg | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | TIBC | 80.7 micrograms per deciliter (μg/dL) | Standard Deviation 39.04 |
| Placebo | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | Iron | -1.5 micrograms per deciliter (μg/dL) | Standard Deviation 26.64 |
| Placebo | Mean Change in Iron and Total Iron Binding Capacity (TIBC) From Baseline to the End of the Primary Efficacy Period | TIBC | 15.8 micrograms per deciliter (μg/dL) | Standard Deviation 8.08 |
Comparison: Ironp-value: 0.9373ANCOVA
Comparison: Ironp-value: 0.6623ANCOVA
Comparison: Ironp-value: 0.9374ANCOVA
Comparison: TIBCp-value: 0.2085ANCOVA
Comparison: TIBCp-value: 0.0016ANCOVA
Comparison: TIBCp-value: 0.0001ANCOVA
Secondary
Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | RBC Count | 0.454 10^6 cells/µL | Standard Deviation 0.2225 |
| Vadadustat 150 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Absolute Reticulocyte Count | 0.017 10^6 cells/µL | Standard Deviation 0.0169 |
| Vadadustat 300 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | RBC Count | 0.819 10^6 cells/µL | Standard Deviation 0.5127 |
| Vadadustat 300 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Absolute Reticulocyte Count | 0.021 10^6 cells/µL | Standard Deviation 0.018 |
| Vadadustat 600 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | RBC Count | 0.503 10^6 cells/µL | Standard Deviation 0.5056 |
| Vadadustat 600 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Absolute Reticulocyte Count | 0.016 10^6 cells/µL | Standard Deviation 0.0162 |
| Placebo | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | RBC Count | 0.065 10^6 cells/µL | Standard Deviation 0.0212 |
| Placebo | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Absolute Reticulocyte Count | 0.016 10^6 cells/µL | Standard Deviation 0.0083 |
| Placebo to Vadadustat 300 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | RBC Count | 1.160 10^6 cells/µL | — |
| Placebo to Vadadustat 300 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Absolute Reticulocyte Count | 0.024 10^6 cells/µL | — |
| Placebo to Vadadustat 600 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | RBC Count | 1.035 10^6 cells/µL | Standard Deviation 0.0778 |
| Placebo to Vadadustat 600 mg | Mean Change in RBC Count and Absolute Reticulocyte Count From Baseline to the End of the Dose Adjustment and Maintenance Period | Absolute Reticulocyte Count | 0.014 10^6 cells/µL | Standard Deviation 0.0217 |
Secondary
Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | RBC Count | -0.01 10^6 cells/microliter (µL) | Standard Error 0.073 |
| Vadadustat 150 mg | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | Absolute Reticulocyte Count | 0.02 10^6 cells/microliter (µL) | Standard Error 0.005 |
| Vadadustat 300 mg | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | Absolute Reticulocyte Count | 0.02 10^6 cells/microliter (µL) | Standard Error 0.004 |
| Vadadustat 300 mg | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | RBC Count | 0.08 10^6 cells/microliter (µL) | Standard Error 0.069 |
| Vadadustat 600 mg | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | RBC Count | 0.20 10^6 cells/microliter (µL) | Standard Error 0.069 |
| Vadadustat 600 mg | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | Absolute Reticulocyte Count | 0.03 10^6 cells/microliter (µL) | Standard Error 0.004 |
| Placebo | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | RBC Count | -0.30 10^6 cells/microliter (µL) | Standard Error 0.099 |
| Placebo | Mean Change in Red Blood Cell (RBC) Count and Absolute Reticulocyte Count From Baseline to the End of the Primary Efficacy Period | Absolute Reticulocyte Count | 0.01 10^6 cells/microliter (µL) | Standard Error 0.006 |
Comparison: RBC Countp-value: 0.023295% CI: [0.04, 0.54]ANCOVA
Comparison: RBC Countp-value: 0.003395% CI: [0.13, 0.62]ANCOVA
Comparison: RBC Countp-value: 0.000295% CI: [0.26, 0.74]ANCOVA
Comparison: Absolute Reticulocyte Countp-value: 0.328994% CI: [-0.01, 0.02]ANCOVA
Comparison: Absolute Reticulocyte Countp-value: 0.260795% CI: [-0.01, 0.02]ANCOVA
Comparison: Absolute Reticulocyte Countp-value: 0.025295% CI: [0, 0.03]ANCOVA
Secondary
Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period | -6.51 percentage | Standard Deviation 11.621 |
| Vadadustat 300 mg | Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period | -10.14 percentage | Standard Deviation 11.294 |
| Vadadustat 600 mg | Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period | -12.46 percentage | Standard Deviation 9.544 |
| Placebo | Mean Change in Transferrin Saturation (TSAT) From Baseline to the End of the Primary Efficacy Period | -2.78 percentage | Standard Deviation 12.822 |
p-value: 0.2708ANCOVA
p-value: 0.0966ANCOVA
p-value: 0.0424ANCOVA
Secondary
Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | -14.25 percentage | Standard Deviation 12.069 |
| Vadadustat 300 mg | Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | -13.79 percentage | Standard Deviation 13.549 |
| Vadadustat 600 mg | Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | -10.93 percentage | Standard Deviation 12.627 |
| Placebo | Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | -12.50 percentage | Standard Deviation 18.526 |
| Placebo to Vadadustat 300 mg | Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | -17.10 percentage | — |
| Placebo to Vadadustat 600 mg | Mean Change in TSAT From Baseline to the End of the Dose Adjustment and Maintenance Period | -4.70 percentage | Standard Deviation 12.021 |
Secondary
Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period
Data are reported as mean of the actual Week 16 values.
Time frame: up to Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | 10.460 g/dL | Standard Deviation 0.7501 |
| Vadadustat 300 mg | Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | 11.285 g/dL | Standard Deviation 1.7841 |
| Vadadustat 600 mg | Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | 11.100 g/dL | Standard Deviation 1.1402 |
| Placebo | Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | 8.600 g/dL | Standard Deviation 0.9899 |
| Placebo to Vadadustat 300 mg | Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | 13.200 g/dL | — |
| Placebo to Vadadustat 600 mg | Mean Hb Levels at the End of the Dose Adjustment and Maintenance Period | 12.100 g/dL | Standard Deviation 1.5556 |
Secondary
Mean Hb Levels at the End of the Primary Efficacy Period
Data are reported as mean of the actual Week 6 values.
Time frame: up to Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Mean Hb Levels at the End of the Primary Efficacy Period | 9.064 g/dL | Standard Deviation 1.0652 |
| Vadadustat 300 mg | Mean Hb Levels at the End of the Primary Efficacy Period | 9.062 g/dL | Standard Deviation 0.8412 |
| Vadadustat 600 mg | Mean Hb Levels at the End of the Primary Efficacy Period | 9.969 g/dL | Standard Deviation 0.7296 |
| Placebo | Mean Hb Levels at the End of the Primary Efficacy Period | 7.817 g/dL | Standard Deviation 1.4662 |
Secondary
Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period
Time frame: up to Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat 150 mg | Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | 7 Participants |
| Vadadustat 300 mg | Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | 11 Participants |
| Vadadustat 600 mg | Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | 7 Participants |
| Placebo | Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo to Vadadustat 300 mg | Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo to Vadadustat 600 mg | Number of Participants Who Achieved the Target Hb Level of 10.0 to 12.0 g/dL at the End of the Dose Adjustment and Maintenance Period | 1 Participants |
Secondary
Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period
Participants who initiated rescue therapy (including RBC transfusion) were required to stop study drug treatment and were discontinued from the study.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat 150 mg | Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period | 0 Participants |
| Vadadustat 300 mg | Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period | 0 Participants |
| Vadadustat 600 mg | Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period | 1 Participants |
| Placebo | Number of Participants Who Required Rescue With a RBC Transfusion From Baseline to the End of the Primary Efficacy Period | 3 Participants |
Secondary
Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period
ESA rescue is defined as participants with ESA administration and 1) the participant experienced a clinically significant worsening of their anemia or symptoms of anemia, 2) the participant's Hb level is \<9.0 g/dL, and 3) reason for early study withdrawal of worsening of anemia requiring ESA rescue or blood transfusion. Participants who initiated rescue therapy (including ESAs) were required to stop study drug treatment and were discontinued from the study.
Time frame: Baseline; Week 6
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat 150 mg | Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period | 4 Participants |
| Vadadustat 300 mg | Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period | 2 Participants |
| Vadadustat 600 mg | Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period | 1 Participants |
| Placebo | Number of Participants Who Required Rescue With Erythropoiesis-Stimulating Agents (ESAs) From Baseline to the End of the Primary Efficacy Period | 8 Participants |
Secondary
Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period
ESA rescue is defined as participants with ESA administration and 1) the participant experienced a clinically significant worsening of their anemia or symptoms of anemia, 2) the participant's Hb level is \<9.0 g/dL, and 3) reason for early study withdrawal of worsening of anemia requiring ESA rescue or blood transfusion. Participants who initiated rescue therapy (including ESAs) were required to stop study drug treatment and were discontinued from the study.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat 150 mg | Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Vadadustat 300 mg | Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Vadadustat 600 mg | Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo | Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 Participants |
| Placebo to Vadadustat 300 mg | Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo to Vadadustat 600 mg | Number of Participants Who Required Rescue With ESAs From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
Secondary
Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period
Participants who initiated rescue therapy (including RBC transfusion) were required to stop study drug treatment and were discontinued from the study.
Time frame: Baseline; Week 16
Population: mITT Population. Only participants with available data were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vadadustat 150 mg | Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 Participants |
| Vadadustat 300 mg | Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Vadadustat 600 mg | Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo | Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo to Vadadustat 300 mg | Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
| Placebo to Vadadustat 600 mg | Number of Participants Who Required Rescue With RBC Transfusion From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 Participants |
Secondary
Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period
An AE was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. An AE that met one or more of the following criteria or outcomes was classified as serious: death; life-threatening; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; was considered a medically important event not meeting the above criteria, but which could jeopardize a participant, or could require medical or surgical intervention to prevent one of the criteria listed in this definition.
Time frame: up to Week 16
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vadadustat 150 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | TEAEs | 9 Participants |
| Vadadustat 150 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | Treatment-emergent SAEs | 1 Participants |
| Vadadustat 300 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | TEAEs | 9 Participants |
| Vadadustat 300 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | Treatment-emergent SAEs | 1 Participants |
| Vadadustat 600 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | TEAEs | 9 Participants |
| Vadadustat 600 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | Treatment-emergent SAEs | 1 Participants |
| Placebo | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | TEAEs | 1 Participants |
| Placebo | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | Treatment-emergent SAEs | 0 Participants |
| Placebo to Vadadustat 300 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | TEAEs | 1 Participants |
| Placebo to Vadadustat 300 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | Treatment-emergent SAEs | 0 Participants |
| Placebo to Vadadustat 600 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | TEAEs | 2 Participants |
| Placebo to Vadadustat 600 mg | Number of Participants With TEAEs and Treatment-emergent SAEs in the Dose Adjustment and Maintenance Period | Treatment-emergent SAEs | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period
An adverse event (AE) was defined as any untoward medical occurrence (including a clinically significant abnormal laboratory finding) that occurred in the protocol-specified AE reporting period. An AE included medical conditions, signs, and symptoms not previously observed in the participant that emerged during the protocol-specified AE reporting period, including signs or symptoms associated with pre-existing underlying conditions that were not present prior to the AE reporting period. An AE that met one or more of the following criteria or outcomes was classified as serious: death; life-threatening; in-patient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; was considered a medically important event not meeting the above criteria, but which could jeopardize a participant, or could require medical or surgical intervention to prevent one of the criteria listed in this definition.
Time frame: up to Week 6
Population: Safety Population: all enrolled participants who received at least 1 dose of study medication. The Safety Population was based on the actual treatment that participants received
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vadadustat 150 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | TEAEs | 8 Participants |
| Vadadustat 150 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | Treatment-emergent SAEs | 0 Participants |
| Vadadustat 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | Treatment-emergent SAEs | 0 Participants |
| Vadadustat 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | TEAEs | 11 Participants |
| Vadadustat 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | TEAEs | 6 Participants |
| Vadadustat 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | Treatment-emergent SAEs | 3 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | TEAEs | 6 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (SAEs) in the Primary Efficacy Period | Treatment-emergent SAEs | 1 Participants |
Secondary
Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period
Increases in dose were not allowed during the 6-week Primary Efficacy Period.
Time frame: up to Week 16
Population: mITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vadadustat 150 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 dose adjustments | 5 Participants |
| Vadadustat 150 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 dose adjustment | 2 Participants |
| Vadadustat 150 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 2 dose adjustments | 5 Participants |
| Vadadustat 150 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 3 or more dose adjustments | 3 Participants |
| Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 2 dose adjustments | 8 Participants |
| Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 dose adjustment | 2 Participants |
| Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 dose adjustments | 3 Participants |
| Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 3 or more dose adjustments | 2 Participants |
| Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 3 or more dose adjustments | 0 Participants |
| Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 2 dose adjustments | 3 Participants |
| Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 dose adjustment | 2 Participants |
| Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 dose adjustments | 9 Participants |
| Placebo | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 dose adjustments | 2 Participants |
| Placebo | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 3 or more dose adjustments | 1 Participants |
| Placebo | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 dose adjustment | 1 Participants |
| Placebo | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 2 dose adjustments | 1 Participants |
| Placebo to Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 2 dose adjustments | 1 Participants |
| Placebo to Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 3 or more dose adjustments | 0 Participants |
| Placebo to Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 dose adjustment | 0 Participants |
| Placebo to Vadadustat 300 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 dose adjustments | 3 Participants |
| Placebo to Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 1 dose adjustment | 0 Participants |
| Placebo to Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 2 dose adjustments | 2 Participants |
| Placebo to Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 3 or more dose adjustments | 0 Participants |
| Placebo to Vadadustat 600 mg | Number of the Participants With the Indicated Number of Dose Adjustments From Baseline to the End of the Dose Adjustment and Maintenance Period | 0 dose adjustments | 3 Participants |
Secondary
Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4
Blood samples were collected for analysis.
Time frame: Week 4, pre-dose
Population: Pharmacokinetic (PK) Population: all participants in the Safety Population (all enrolled participants who received at least 1 dose of study medication) who had a pre-dose PK sample at Week 4
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Vadadustat 150 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | O-glucuronide | 8667.97 μg/mL | Geometric Coefficient of Variation 73.79 |
| Vadadustat 150 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Vadadustat | 4343.54 μg/mL | Geometric Coefficient of Variation 175.17 |
| Vadadustat 150 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Acyl-glucuronide | 12.019 μg/mL | Geometric Coefficient of Variation 16.55 |
| Vadadustat 300 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | O-glucuronide | 14623.89 μg/mL | Geometric Coefficient of Variation 67.44 |
| Vadadustat 300 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Vadadustat | 7561.36 μg/mL | Geometric Coefficient of Variation 134.77 |
| Vadadustat 300 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Acyl-glucuronide | 12.174 μg/mL | Geometric Coefficient of Variation 8.1 |
| Vadadustat 600 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Vadadustat | 15083.03 μg/mL | Geometric Coefficient of Variation 46.77 |
| Vadadustat 600 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | Acyl-glucuronide | 22.765 μg/mL | Geometric Coefficient of Variation 70.53 |
| Vadadustat 600 mg | Plasma Concentration Profile of Vadadustat and Its Metabolites Using a Pre-dose Sample From Week 4 | O-glucuronide | 36476.33 μg/mL | Geometric Coefficient of Variation 57.18 |
Secondary
Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16
Time for this analysis was measured from Day 1 (Baseline) through the point in time during either the Primary Efficacy Period or the Dose Adjustment and Maintenance Period when a participant's Hb level achieved the target range of 10.0 to 12.0 g/dL.
Time frame: from Baseline up to Week 16
Population: mITT Population. Only participants with Hb \< 10.0 g/dL at the Baseline visit were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vadadustat 150 mg | Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | 69.3 days | Standard Deviation 25.31 |
| Vadadustat 300 mg | Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | 79.2 days | Standard Deviation 24.94 |
| Vadadustat 600 mg | Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | 54.6 days | Standard Deviation 27.9 |
| Placebo to Vadadustat 300 mg | Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | 57.0 days | Standard Deviation 19.8 |
| Placebo to Vadadustat 600 mg | Time to Reach the Target Hb Level of 10.0 to 12.0 g/dL From Baseline up to Week 16 | 85.0 days | — |