| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia in chronic kidney disease patients without dialysis. |
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| E.1.1.1 | Medical condition in easily understood language |
| Anemia in patients with severe renal disease without dialysis. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluate the cardiovascular (CV) safety of roxadustat for the treatment of anemia in patients with chronic kidney disease (CKD) not on dialysis therapy. |
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| E.2.2 | Secondary objectives of the trial |
Evaluate the efficacy of roxadustat.
Evaluate the CV safety of roxadustat for the composite endpoint of all cause mortality, non-fatal Myocardial Infarction (MI), non-fatal stroke, heart failure requiring hospitalization and unstable angina leading to hospitalization
Evaluate the CV safety of roxadustat for the composite safety endpoint (CSE) of all cause mortality, non-fatal MI, non-fatal stroke, heart failure requiring hospitalization, unstable angina leading to hospitalization, deep vein thrombosis, pulmonary embolism, vascular access thrombosis or hypertensive emergency
Evaluate the need for rescue therapy
CKD progression
Evaluate the effect of roxadustat on anemia symptoms and health-related quality of life (HRQoL)
Evaluate the effect of roxadustat on self-reported health status.
To evaluate the safety and tolerability of roxadustat
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| -Age ≥18 years. - 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. - 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.- Ferritin ≥50 ng/mL at randomization. - Transferrin saturation ≥15% at randomization. - Serum folate level ≥ lower limit of normal (LLN) at randomization. - Serum vitamin B12 level ≥LLN at randomization. - Alanine aminotransferase and aspartate aminotransferase ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.5 x ULN at randomization. - Body weight 45 to 160 kg. |
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| E.4 | Principal exclusion criteria |
| -Any erythropoietin analogue treatment within 6 weeks of randomization.- New York Heart Association Class III or IV congestive heart failure at enrollment- Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.- History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver).- 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.- Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis).- 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.- Systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥95 mmHg, within 2 weeks prior to randomization. Patients may be rescreened once BP controlled.- 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.- Positive for any of the following: human immunodeficiency virus, hepatitis B surface antigen or anti-hepatitis C virus antibody.- 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.- Known hemosiderosis, hemochromatosis or hypercoagulable condition.- Any prior organ transplant or a scheduled organ transplantation date.- Any red blood cell transfusion during the screening period.- Any current condition leading to active significant blood loss.- Any treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor.- 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).- History of alcohol or drug abuse within 2 years prior to randomization. - Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence. - Pregnant or breastfeeding females.- Known allergy to the investigational product or any of its ingredients.- 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Major adverse cardiovascular (CV) events (MACE): Time to first occurrence of all cause mortality, non-fatal myocardial infarction or non-fatal stroke. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From randomization (week 0) to end of study (event-driven, anticipate 1-2 years).
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| E.5.2 | Secondary end point(s) |
1. Mean change in hemoglobin (Hb) from baseline to the end of treatment visit (event-driven, anticipate 1-2 years).
2. Proportion of total time of Hb measurements within the interval of 11±1 g/dL from week 28 until end of treatment visit (event-driven, anticipate 1-2 years).
3. MACE+: Time to first occurrence of all cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke, heart failure requiring hospitalization or unstable angina leading to hospitalization.
4. Time to first occurrence of all cause mortality, non-fatal MI, non-fatal stroke, heart failure requiring hospitalization, unstable angina leading to hospitalization, deep vein thrombosis, pulmonary embolism, vascular access thrombosis or hypertensive emergency.
5. Time-to-first instance of receiving intravenous (IV) iron, red blood cell (RBC) transfusions or erythropoietin analogue as rescue therapy.
6.Change in estimated glomerular filtration rate (eGFR) from baseline to the end of treatment visit(event-driven, anticipate 1-2 years).
7. Changes in anemia symptoms and four disease-specific Health Related Quality of Life (HRQoL) domains as measured by the Funtional Assessment of Cancer Therapy-Anemia (FACT-An). Measured at visit randomization (week 0), week 12, 28 and 52.
8.Changes in generic HRQoL as measured by the Short Form 36 (SF-36) (vers 2, standard). Measured at visit randomization (week 0), week 12, 28 and 52.
9. Changes in self-reported health status as measured by the EuroQol Health Utility Index (EQ-5D-5L) and Patients’ Global Impression of Change (PGIC) measured at baseline, week 12, 28 and 52.
10. Adverse events (AEs), serious adverse events (SAEs) and changes in vital signs, electrocardiogram (ECG) and laboratory values. Measured from the first screening visit to the end of the study (event-driven, anticipated duration 1-2 years). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From baseline to end of study (event-driven, anticipate 1-2 years).
2. From week 28 until end of study (event-driven, anticipate 1-2 years).
3. From randomization (week 0) to end of study (event-driven, anticipate 1-2 years).
4.From randomization (week 0) to end of study (event-driven, anticipate 1-2 years).
5. From randomization (week 0) to end of study (event-driven, anticipate 1-2 years).
6. From baseline to end of study (event-driven, anticipate 1-2 years).
7. Measured at visit randomization (week 0), week 12, 28 and 52.
8. Measured at visit randomization (week 0), week 12, 28 and 52.
9. At baseline, week 12, 28 and week 52
10.From the first screening visit to the end of the study (event-driven, anticipated duration 1-2 years). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Evaluate self-reported health status.
Evaluate the need for rescue therapy.
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|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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