NCT02174627

Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis

Completed Phase 3 Results posted Last updated 16 December 2019

What this trial tests

Phase 3 trial testing Roxadustat in Anemia in 2,781 participants. Completed in 4 October 2018.

Timeline

26 June 2014

Primary endpoint
4 October 2018

4 October 2018

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	2,781
Start date	26 June 2014
Primary completion	4 October 2018
Estimated completion	4 October 2018
Sites	359 locations across Colombia, Malaysia, Taiwan, Vietnam, Poland, South Korea, Philippines, Russia

Drugs / interventions tested

• Roxadustat (ROXADUSTAT) — full drug profile →
• Placebo

Conditions studied

• Anemia — all drugs for Anemia →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 130, any sex, with Anemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 Primary · Baseline (Day 1, Week 0) and Week 28 to Week 52.

Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation analysis of covariance (ANCOVA) model with baseline Hb, baseline estimated glomerular filtration rate (eGFR), cardiovascular (CV) history, geographic region and treatment group as fixed effect covariates. The adjusted least squares (LS) mean estimates of change from baseline to mean during Week 28 to Week 52 are presented.

Group	Value	95% CI
Roxadustat	1.75	± 0.033
Placebo	0.40	± 0.034

Percentage of Participants With Hb Response During the First 24 Weeks of Treatment Secondary · Baseline (Day 1, Week 0) up to Week 24.

Hb response was defined as: * Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL for participants with baseline Hb \> 8.0 g/dL; or * Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at 2 consecutive visits (with available data) separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell \[RBC\] transfusion, erythropoietin analogue, or intravenous \[IV\] iron) prior to Hb response. The percentage of participants with an Hb response during the first 24 weeks of treatment is presented.

Group	Value	95% CI
Roxadustat	77.0
Placebo	8.5

Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN) Secondary · Baseline (Day 1, Week 0) and Week 28 to Week 52.

Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value during Week 28 to Week 52 was analyzed using a MAR based multiple imputation ANCOVA model with baseline Hb, baseline eGFR, CV history, geographic region and treatment group as fixed effect covariates. The adjusted LS mean estimates of change from baseline in participants with baseline hsCRP \>ULN to mean during Week 28 to Week 52 are present

Group	Value	95% CI
Roxadustat	1.75	± 0.087
Placebo	0.62	± 0.091

Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52 Secondary · Week 28 up to Week 52.

Proportion of total time of interpolated Hb values ≥10 g/dL was calculated as the time the linearly interpolated curve between measurements ≥10 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.

Group	Value	95% CI
Roxadustat	0.82	± 0.011
Placebo	0.33	± 0.011

Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52 Secondary · Week 28 up to Week 52.

Proportion of total time of interpolated Hb values within the interval of 10 to 12 g/dL was calculated as the time the linearly interpolated curve between measurements were within 10 to 12 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.

Group	Value	95% CI
Roxadustat	0.70	± 0.010
Placebo	0.28	± 0.010

Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24 Secondary · Baseline (Day 1, Week 0) and Week 24

Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analyzed using an ANCOVA model with baseline LDL, baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.

Group	Value	95% CI
Roxadustat	-0.38	± 0.028
Placebo	-0.02	± 0.027

Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy Secondary · Baseline (Day1, Week 0) up to End of Study (EOS) visit (4 weeks after the treatment period) (or up to date of first rescue therapy), with treatment duration up to 4 years.

Time-to-first rescue therapy (IV iron, RBC transfusion or erythropoietin analogue) was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.

Group	Value	95% CI
Roxadustat	11.90
Placebo	39.76

Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy Secondary · Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period) (or up to date of first RBC rescue therapy), with treatment duration up to 4 years.

Time-to-first RBC rescue therapy was calculated as (date of first RBC rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.

Group	Value	95% CI
Roxadustat	7.98
Placebo	19.61

Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28 Secondary · Baseline (Day 1, Week 0) and Week 12 to Week 28.

SF-36 is a Quality of Life (QoL) scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Vitality sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a mixed model for repeated measures (MMRM) with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region,

Group	Value	95% CI
Roxadustat	1.59	± 0.231
Placebo	1.15	± 0.233

Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant Secondary · Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years.

Baseline eGFR was defined as the mean of all available central laboratory values prior to or at randomization. Rate of change in eGFR from baseline during the entire treatment period (in millilitres/minute/1.73 meters squared/years \[mL/min/1.73m\^2/years\]) was estimated using a random effects model using all post-baseline eGFR values prior to initiation of dialysis/transplant. Baseline eGFR, baseline Hb, geographic region, CV history, treatment group and post-baseline eGFR measurement time were used as fixed effects and participant and time (years) as random effects, ie, random intercept and

Group	Value	95% CI
Roxadustat	-3.70
Placebo	-3.19

Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28 Secondary · Baseline (Day 1, Week 0) and Week 12 to Week 28.

SF-36 is a QoL scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Physical Functioning sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a MMRM with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction a

Group	Value	95% CI
Roxadustat	0.14	± 0.222
Placebo	-0.39	± 0.224

Adverse events — posted to ClinicalTrials.gov

Time frame: From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Roxadustat

Serious: 795/1384 (57%)

Deaths: 284/1384

Placebo

Serious: 749/1377 (54%)

Deaths: 245/1377

Serious adverse events (755 terms)

Reaction	System	Roxadustat	Placebo
End stage renal disease	Renal and urinary disorders	—	—
Pneumonia	Infections and infestations	—	—
Azotaemia	Renal and urinary disorders	—	—
Sepsis	Infections and infestations	—	—
Death	General disorders	—	—
Hyperkalaemia	Metabolism and nutrition disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Hypertensive crisis	Vascular disorders	—	—
Cardiac failure	Cardiac disorders	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Cellulitis	Infections and infestations	—	—
Fluid overload	Metabolism and nutrition disorders	—	—
Acute pulmonary oedema	Respiratory, thoracic and mediastinal disorders	—	—
Hypertensive emergency	Vascular disorders	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Gastritis	Gastrointestinal disorders	—	—
Septic shock	Infections and infestations	—	—
Arteriovenous fistula thrombosis	Injury, poisoning and procedural complications	—	—
Generalised oedema	General disorders	—	—
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	—	—
Hypertension	Vascular disorders	—	—

Other adverse events (19 terms — click to expand)

Reaction	System	Roxadustat	Placebo
Urinary tract infection	Infections and infestations	—	—
Hypertension	Vascular disorders	—	—
Oedema peripheral	General disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Headache	Nervous system disorders	—	—
End stage renal disease	Renal and urinary disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Hyperkalaemia	Metabolism and nutrition disorders	—	—
Dizziness	Nervous system disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Bronchitis	Infections and infestations	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—

Most-reported serious reactions: End stage renal disease, Pneumonia, Azotaemia, Sepsis, Death, Hyperkalaemia, Acute kidney injury, Urinary tract infection.

Data from ClinicalTrials.gov NCT02174627 adverse events section.

Sponsor's own description

The purpose of the study is to evaluate the safety and efficacy of roxadustat for treatment of anemia in patients with chronic kidney disease not on dialysis

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Anaemia in kidney disease: harnessing hypoxia responses for therapy.
   Koury MJ, Haase VH. · · 2015 · cited 245× · PMID 26055355 · DOI 10.1038/nrneph.2015.82
2. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience.
   Sanghani NS, Haase VH. · · 2019 · cited 139× · PMID 31477256 · DOI 10.1053/j.ackd.2019.04.004
3. Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.
   Fishbane S, El-Shahawy MA, Pecoits-Filho R, Van BP, et al · · 2021 · cited 127× · PMID 33568383 · DOI 10.1681/asn.2020081150
4. Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease.
   Haase VH. · · 2021 · cited 115× · PMID 33777492 · DOI 10.1016/j.kisu.2020.12.002
5. Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin.
   Hanna RM, Streja E, Kalantar-Zadeh K. · · 2021 · cited 114× · PMID 33123967 · DOI 10.1007/s12325-020-01524-6
6. The hypoxia-adenosine link during inflammation.
   Bowser JL, Lee JW, Yuan X, Eltzschig HK. · · 2017 · cited 90× · PMID 28798196 · DOI 10.1152/japplphysiol.00101.2017
7. Roxadustat Treatment of Chronic Kidney Disease-Associated Anemia in Japanese Patients Not on Dialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.
   Akizawa T, Iwasaki M, Otsuka T, Reusch M, et al · · 2019 · cited 72× · PMID 30953333 · DOI 10.1007/s12325-019-00943-4
8. Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non-Dialysis-Dependent CKD: Pooled Results of Three Randomized Clinical Trials.
   Provenzano R, Szczech L, Leong R, Saikali KG, et al · · 2021 · cited 64× · PMID 34362786 · DOI 10.2215/cjn.16191020