| 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 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| 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 |
Primary Efficacy Objective: Evaluate the efficacy of Roxadustat for the treatment of anemia in CKD subjects on dialysis.
Primary Safety Objective: Contribute CV safety data to pooled safety analyses across the phase 3 program |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objectives:
- The efficacy of roxadustat as compared to epoetin alfa based on Hb response and level during the study
- The effect of roxadustat on Low-density lipoprotein (LDL) cholesterol as compared to epoetin alfa
- The efficacy of roxadustat based on Hb response in inflamed subjects
- The need for IV iron use in subjects treated with roxadustat as compared to epoetin alfa
- The need for RBC transfusion as rescue therapy in subjects treated with roxadustat as compared to epoetin alfa
Secondary Safety Objectives:
- To evaluate the safety and tolerability of roxadustat. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of Informed Consent prior to any study specific procedures
2. Age ≥18 years at screening visit 1
3. Previous versions of the protocol prior to US amendment ver 6.0 and outside of US amendment ver 7.0:
- Receiving or initiating hemodialysis or peritoneal dialysis for treatment of native kidney end-stage renal disease (ESRD) at least 30 days prior to visit 1. 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.
Starting with US amendment ver. 6.0 and outside of US amendment ver 7.0 (changed to recruit incident dialysis patients only):
- 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.
4. 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 analogue or <10 g/dL in patients not currently treated with an erythropoietin analogue. Patients are considered not currently treated if they have not received either Mircera® for at least 8 weeks or any other erythropoietin analogue for at least 4 weeks prior to visit 1.
5. Ferritin ≥100 ng/mL at randomization (obtained from screening visit)
6. TSAT ≥20% at randomization (obtained from screening visit)
7. Serum folate level ≥ lower limit of normal (LLN) at randomization (obtained from screening visit)
8. Serum vitamin B12 level ≥ LLN at randomization (obtained from screening visit)
9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN), and total bilirubin (Tbili) ≤1.5 x ULN at randomization (obtained from screening visit)
10. Body weight 45 to 160 kg (prescribed dry weight) |
|
| E.4 | Principal 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 randomisation in the present study
3. New York Heart Association Class III or IV congestive heart failure at enrolment
4. 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
5. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis or fibrosis of the liver)
6. 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
7. Known and untreated retinal vein occlusion or known and untreated proliferative diabetic retinopathy (risk for retinal vein thrombosis)
8. 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. CT scan or MRI) conducted at screening or within 12 weeks prior to randomization.
9. 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)
10. 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.
11. Positive for any of the following: human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus antibody (anti-HCV Ab)
12. Chronic inflammatory diseases such as rheumatoid arthritis, SLE, ankylosing spondylitis, psoriatic arthritis or inflammatory bowel disease that is determined to be the principal cause of anemia
13. Known hemosiderosis, hemochromatosis or hypercoagulable condition
14. Any prior organ transplant with the exception of an autologous renal transplant or a renal transplant that was subsequently removed (“explanted”) or scheduled organ transplantation date
15. Any red blood cell (RBC) transfusion during the screening period
16. Any current condition leading to active significant blood loss
17. Any prior treatment with roxadustat or a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI)
18. 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 the month preceding the first administration of IP in this study. (Note: patients consented and screened, but not randomized in this study or a previous study are not excluded)
19. History of alcohol or drug abuse within 2 years prior to randomization
20. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence (see Section 3.8)
21. Pregnant or breastfeeding females
22. Known allergy to the investigational product or any of its ingredients
23. 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 efficacy or safety assessment, or may interfere with study participation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
- US FDA: Mean change from baseline in Hb averaged over week 28 to week 52.
- EU health authorities: The EU (EMA) primary efficacy endpoint is change in Hb from BL to the average level during the evaluation period (defined as week 28 until week 36), without having received rescue therapy (i.e. RBC transfusion for all subjects or ESA for subjects treated with roxadustat) within 6 weeks prior to and during this 8-week evaluation period.
Primary Safety Endpoint:
Adjudicated CV safety data. Analyses of the adjudicated events are described in a separate pooled statistical analysis plan. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Endpoint:
- US FDA: From week 28 to week 52.
- EU health authorities: From week 28 to week 36.
Primary Safety Endpoint: Analyses of the adjudicated events are described in a separate pooled statistical analysis plan. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
1. The EU primary endpoint is the first secondary efficacy endpoint for FDA.
2. Mean change from baseline in LDL cholesterol from baseline to week 24
3. 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)
4. Proportion of total time of Hb ≥ 10 g/dL from week 28 to week 52.
5. Proportion of total time of Hb within the interval of 10-12 g/dL from week 28 to week 52
6. Average monthly IV iron use
7. Time-to-first (and proportion of subjects receiving) administration of red blood cell (RBC) transfusion as rescue therapy
Secondary Safety Endpoints:
Adverse events (AEs), serious adverse events (SAEs).
Changes in vital signs, electrocardiogram (ECG) and laboratory values. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoints:
1. From week 28 to week 36.
2. From randomization to week 24.
3. From week 28 to week 52.
4. From week 28 to week 52.
5. From week 28 to week 52.
6. From week 36 to End of Study (EOS).
7. From the first date of study drug (SD) intake to EOS for subjects without SD discontinuation (SDD) or to the last SD intake for SDD subjects.
Safety Endpoints:
From date of first dose of SD to 28 days after last dose of SD. |
|
| 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 | 71 |
| 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 | Yes |
| 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
|
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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