| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia in chronic kidney disease patients with dialysis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anemia in patients with severe renal disease with 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 | 20.0 |
| 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 |
|
| 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 efficacy of roxadustat for the treatment of anemia in CKD subjects on dialysis
Evaluate the cardiovascular (CV) safety of roxadustat based on comparison with epoetin alfa for the composite endpoint of all cause
mortality, non-fatal myocardial infarction and non-fatal stroke |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the efficacy of roxadustat as compared to epoetin alfa
Evaluate the CV safety of roxadustat based on comparison with epoetin alfa for the composite endpoint of all cause mortality, non-fatal myocardial infarction, non-fatal stroke, heart failure requiring hospitalization and unstable angina leading to hospitalization
Evaluate the CV safety of roxadustat based on comparison with epoetin alfa for the composite safety endpoint (CSE) of all cause mortality, non-fatal myocardial infarction, non-fatal stroke, heart failure leading to hospitalization, unstable angina requiring hospitalization, vascular access thrombosis, deep vein thrombosis, pulmonary embolism or hypertensive emergency.
Evaluate the need for rescue therapy in patients treated with roxadustat as compared to epoetin alfa
Evaluate self-reported health status in patients treated with roxadustat as compared to epoetin alfa
To assess the safety and tolerability of roxadustat as compared to epoetin alfa
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age ≥18 years
- Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) for a minimum of 2 weeks and a maximum of 4 months prior to randomization. Patients treated with hemodialysis must have access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter. Patients on peritoneal dialysis must have a functioning peritoneal dialysis catheter in place.
- Two central laboratory Hb values during the screening period, obtained at least 7 days apart, must be <12 g/dL in patients currently treated with an erythropoietin analouge or <10 g/dL in patients not currently treated with an erythropoietin analouge. Patients are considered not currently treated if they have not received either Mircera® for at least 8 weeks or any other erythropoietin analouge for at least 4 weeks prior to visit 1.
- Ferritin ≥100 ng/mL at randomization.
- Transferrin saturation (TSAT) ≥20% at randomization.
- Serum folate level ≥ lower limit of normal (LLN) at randomization.
- Serum vitamin B12 level ≥LLN at randomization.
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN), and total bilirubin ≤1.5 x ULN at randomization.
- Body weight 45 to 160 kg. |
|
| E.4 | Principal exclusion criteria |
| - New York Heart Association Class III or intravenous (IV) congestive heart failure at enrollment - Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic 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 chronic kidney disease (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 (CT) scan or magnetic resonance imaging (MRI)) conducted at screening or within 12 weeks prior to randomization. - Uncontrolled hypertension at the time of randomization, (defined as systolic BP ≥180 mmHg or diastolic BP ≥100 mmHg on repeated measurement post-dialysis in hemodialysis patients or at any time in peritoneal dialysis patients), contraindication to epoetin alfa treatment (e.g., pure red cell aplasia, hypersensitivity or know inability to tolerate epoetin alfa). - 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 (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody. - Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be principal cause of anemia. - Known hemosiderosis, hemochromatosis or hypercoagulable condition. - Any prior organ transplant with the exception of a renal transplant that was subsequently removed (“explanted”) or scheduled organ transplantation date. - Any red blood cell (RBC) transfusion during the screening period. - Any current condition leading to active significant blood loss. - Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). - 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Major adverse cardiovascular (CV) events (MACE): Time to first occurrence of death from any cause, non-fatal myocardial infarction or non-fatal stroke.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomization (week 0) to week 52.
From randomization (week 0) to end of study (event-driven, anticipate up to 4 years).
|
|
| E.5.2 | Secondary end point(s) |
1. Proportion of total time of Hb measurements within the interval of 11±1 g/dL from week 28 until end of treatment visit.
2. Time to first rescue therapy (composite of erythropoietin analogue therapy [for roxadustat-allocated patients only] or RBC transfusion).
3.Changes in self-reported health status as measured by the EuroQol Health Utility Index (EQ-5D-5L) during roxadustat or epoetin alfa treatment.
4. Major adverse CV events+ (MACE+): Time to first occurrence of death from any cause, non-fatal myocardial infarction (MI), non-fatal stroke, heart failure requiring hospitalization or unstable angina leading to hospitalization.
5. Time to first occurrence of death from any cause, non-fatal MI, nonfatal stroke, heart failure requiring hospitalization, unstable angina leading to hospitalization, vascular access thrombosis, deep vein thrombosis, pulmonary embolism or hypertensive emergency.
6. Adverse events (AEs), serious adverse events (SAEs) Changes in vital signs, electrocardiogram (ECG) and laboratory values. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From week 28 until end of study.
2. From randomization (week 0) to end of study (event-driven, anticipate up to 4 years).
3. At baseline, week 12, 28 and 52.
4. From randomization (week 0) to end of study (event-driven, anticipate up to 4 years).
5. From randomization (week 0) to end of study (event-driven, anticipate up to 4 years).
6. From the first screening visit to the end of the study (event-driven, anticipate up to 4 years). |
|
| 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 in patients treated with roxadustat as compared to EPO |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 71 |
| 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 |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| Czech Republic |
| Hungary |
| India |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Thailand |
| Ukraine |
| United States |
| Vietnam |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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