Safety and efficacy study of roxadustat to treat anemia in patients with chronic kidney disease (CKD), not on dialysis.

• Register: EUCTR
• Last refreshed on: 7 January 2019
• Main ID: EUCTR2014-000770-19-SK
• Date of registration: 27/10/2014
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: Safety and efficacy study of roxadustat to treat anemia in patients with chronic kidney disease (CKD), not on dialysis.
• Scientific title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients not on Dialysis
• Date of first enrolment: 10/12/2014
• Target sample size: 2600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000770-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Brazil, Bulgaria, Canada, Czech Republic, Germany, Hungary, India, Italy, Korea, Republic of, Mexico, Peru, Philippines, Poland, Romania, Russian Federation, Slovakia, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Vietnam

Contacts

• Name: Information Centre
• Affiliation: AstraZeneca AB

• Name: Information Centre
• Affiliation: AstraZeneca AB

Key inclusion & exclusion criteria

Inclusion criteria:
1) Provision of informed consent prior to any study specific procedures
2) Age =18 years.
3) A glomerular filtration rate (eGFR) <60 mL/min/1.73 m2,
corresponding to stage 3, 4 or 5 chronic kidney disease (CKD) according
to the Kidney Disease Outcomes Quality Initiative, not receiving dialysis.
4) Mean of 2 most recent central laboratory hemoglobin (Hb) values
during the screening period, obtained at least 7 days apart, must be
<10.0 g/dL.
5) Ferritin =50 ng/mL at randomization.
6) Transferrin saturation =15% at randomization.
7) Serum folate level = lower limit of normal (LLN) at randomization.
8) Serum vitamin B12 level =LLN at randomization.
9) Alanine aminotransferase and aspartate aminotransferase =3 x upper
limit of normal (ULN) and total bilirubin =1.5 x ULN at randomization.
10) Body weight 45 to 160 kg.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1300
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1300

Exclusion criteria:
1) Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2) Previous randomization in the present study
3) Any erythropoietin analogue treatment within 6 weeks of randomization.
4) New York Heart Association Class III or IV congestive heart failure at enrollment
5) Myocardial infarction (MI), acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization 6) History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver)
7) Known hereditary hematologic disease such as thalassemia, sickle cell anemia, a history of pure red cell aplasia or other known causes for anemia other than CKD.
8) Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis).
9) Diagnosis or suspicion (e.g. complex kidney cyst of Bosniak Category IIF, III or IV) of renal cell carcinoma on renal ultrasound (or other imaging procedure e.g. computerized tomography scan or magnetic resonance imaging conducted at screening or within 12 weeks prior to randomization.
10) Systolic blood pressure (BP) =160 mmHg or diastolic BP =95 mmHg, within 2 weeks prior to randomization. Patients may be rescreened once BP controlled.
11) History of prostate cancer, breast cancer or any other malignancy, except the following: cancers determined to be cured or in remission for =5 years, curatively resected basal cell or squamous cell skin cancers, cervical cancer in situ, or resected colonic polyps.
12) Positive for any of the following: human immunodeficiency virus, hepatitis B surface antigen or anti-hepatitis C virus antibody.
13) Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia.
14) Known hemosiderosis, hemochromatosis or hypercoagulable condition
15) Any prior organ transplant or a scheduled organ transplantation date
16) Any red blood cell transfusion (RBC) during the screening period
17) Any current condition leading to active significant blood loss.
18) Any treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI).
19) Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within at least 1 month of the first administration of investigation product in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded).
20) History of alcohol or drug abuse within 2 years prior to randomization.
21) Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
22) Pregnant or breastfeeding females.
23) Known allergy to the investigational product or any of its ingredients.
24) Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound safety or efficacy assessment or may interfere with study participation.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Anemia in chronic kidney disease patients without dialysis.
MedDRA version: 20.0 Level: LLT Classification code 10076410 Term: Chronic kidney disease stage 3 System Organ Class: 100000004857
MedDRA version: 20.0 Level: LLT Classification code 10076412 Term: Chronic kidney disease stage 5 System Organ Class: 100000004857
MedDRA version: 20.0 Level: LLT Classification code 10076411 Term: Chronic kidney disease stage 4 System Organ Class: 100000004857

Intervention(s)

Product Code: AZD9941
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Roxadustat
CAS Number: 808118-40-3
Current Sponsor code: AZD9941
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Code: AZD9941
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Roxadustat
CAS Number: 808118-40-3
Current Sponsor code: AZD9941
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Code: AZD9941
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Roxadustat
CAS Number: 808118-40-3
Current Sponsor code: AZD9941
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Primary Efficacy Objective: Evaluate the efficacy of roxadustat compared to placebo for the treatment of anemia in CKD subjects not on dialysis.
Primary Safety Objective: Contribute CV safety data to pooled safety analyses across the phase 3 program

Secondary Objective: Secondary Efficacy Objectives:
- The efficacy of roxadustat compared to placebo based on Hb response and level during the study
- The efficacy of roxadustat compared to placebo based on Hb response in inflamed subjects
- The effect of roxadustat compared to placebo on Low-density lipoprotein (LDL) cholesterol
- The need for rescue therapy in subjects treated with roxadustat as compared to placebo
- The effect of roxadustat on anemia symptoms and health-related quality of life (HRQoL) based on comparison with placebo
- The effect on the CKD progression of roxadustat as compared to placebo

Secondary Safety Objectives:
- To evaluate the safety and tolerability of roxadustat.

Primary end point(s): Primary Efficacy Endpoint:
US FDA: The primary efficacy endpoint for the US is the mean change from baseline in Hb averaged over week 28 to week 52.
EU health authorities: The primary efficacy endpoint is whether patients achieved Hb response (Yes/No) where Yes is defined as: o Hb = 11.0 g/dL and Hb increase from baseline by = 1.0 g/dL, for subjects with baseline Hb > 8.0 g/dL;
or
o Hb increase from baseline by = 2.0 g/dL, for subjects with baseline Hb = 8.0 g/dL at two consecutive visits [dates] (with available data) separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (RBC transfusion, ESA, or IV iron) prior to Hb response.
Primary Safety Endpoint:
Adjudicated CV safety data. Analyses of the adjudicated events are described in a separate pooled statistical analysis plan.

Timepoint(s) of evaluation of this end point: Primary Efficacy Endpoint:
US FDA: From week 28 to week 52.
EU health authorities: From week 0 to week 24.

Primary Safety Endpoint:
Analyses of the adjudicated events are described in a separate pooled statistical analysis plan.

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy Endpoints:
1) Hb response as noted for EU Primary Endpoint.
2) Mean change in Hb from baseline to the subjects mean level between week 28 to week 52 in subjects with baseline high-sensitivity C-reactive protein (hsCRP) greater than the Upper Limit Normal (ULN)
3) Proportion of total time of Hb = 10 g/dL from week 28 to week 52.
4) Proportion of total time of Hb within the interval of 10-12 g/dL from week 28 to week 52
5) Mean change in LDL cholesterol from baseline to week 24
6) Time-to-first (and proportion of subjects receiving) instance of receiving intravenous (IV) iron, red blood cell (RBC) transfusions, or erythropoietin analogue as rescue therapy.
7) Time-to-first (and proportion of subjects receiving) instance of receiving red blood cell (RBC) transfusions as rescue therapy.
8) Change from baseline in SF-36 Vitality (VT) sub-score
9) Annual rate of eGFR change in log scale, calculated as the linear slope of log (eGFR values) to prior to initiation of dialysis/kidney transplant
10) Change from baseline in SF-36 Physical Functioning (PF) sub-score
Secondary Safety Endpoints:
Adverse events (AEs), serious adverse events (SAEs).
Changes in vital signs, electrocardiogram (ECG) and laboratory values.

Timepoint(s) of evaluation of this end point: Efficacy Endpoints
1) From randomization to week 24
2) From week 28 to week 52
3) From week 28 to week 52
4) From week 28 to week 52
5) From randomization to week 24
6) From the first date of study drug (SD) intake to EOS for subjects without SD discontinuation (SDD) or to the last date plus 28 days of SD intake for SDD subjects.
7) From the first date of study drug (SD) intake to EOS for subjects without SD discontinuation (SDD) or to the last date plus 28 days of SD intake for SDD subjects.
8) From week 12 to week 28
9) From randomization to EOS for subjects without initiation of
Dialysis/Transplant (ID/T) or to the date of ID/T for subjects having these renal events.
10) From week 12 to week 28
Safety Endpoints:
From date of first dose of SD to 28 days after last dose of SD

Secondary ID(s)

D5740C00001

2014-000770-19-CZ

NCT02174627

Source(s) of Monetary Support

AstraZeneca AB