| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia due to end-stage renal disease in incident-dialysis patients. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Anemia due to end-stage renal disease in incident-dialysis patients. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10054606 |
| E.1.2 | Term | Secondary anemia |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 and safety ofroxadustat in the treatment of anemia in incident-dialysis subjects compared to Active Control. |
|
| E.2.2 | Secondary objectives of the trial |
- Evaluate the utilization of intravenous (IV) iron with roxadustat
compared to Active Control.
- Evaluate effect of roxadustat on serum lipid parameters compared to
Active Control.
- Evaluate the effect of roxadustat on blood pressure (BP) compared to
Active Control.
- Evaluate time to achieve hemoglobin (Hb) response compared to Active
Control. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Subject has been informed of the investigational nature of this study and has given written informed consent in accordance with institutional, local, and national guidelines.
3. Receiving HD or PD for ESRD for a minimum of 2 weeks and a maximum of 4 months, prior to randomization.
4. Hemodialysis access consisting of an arteriovenous (AV) fistula, AV graft, or tunnelled (permanent) catheter; or PD catheter in use.
5. Mean of the two most recent predialysis Hb values during the Screening Period, obtained at least 2 days apart, must be ≤ 10.0 g/dL, with a difference of ≤ 1.3 g/dL between the highest and the lowest values. The last Hb value must be drawn within 10 days prior to randomization.
6. Ferritin ≥ 100 ng/mL (≥ 220 pmol/L); subjects with ferritin level < 100
ng/mL(<220pmol/L) during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest ferritin prior to randomization.
7. Transferrin saturation ≥ 20%; subjects with TSAT level < 20% during screening, qualify after receiving iron supplement (per local standard of care), without the need to retest TSAT prior to randomization.
8. Serum folate level, performed within 8 weeks prior to randomization ≥ lower limit of normal (LLN); subjects with serum folate level < LLN during screening, qualify after receiving folate supplement (per local standard of care), without the need to retest folate prior to randomization.
9. Serum vitamin B12 level, performed within 8 weeks prior to randomization ≥ LLN; subjects with vitamin B12 level < LLN during screening, qualify after receiving B12 supplement (per local standard of care), without the need to retest B12 prior to randomization.
10. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN), and total bilirubin (Tbili) ≤ 1.5 x ULN.
11. Body weight up to 160 kg (HD subjects: dry weight). |
|
| E.4 | Principal exclusion criteria |
1. Total duration of prior effective ESA use must be ≤3 weeks within the preceding 12 weeks at the time informed consent is obtained.
Specific dosing guidance, depending on the type of ESAs, injected IV or SC within 12 weeks prior to start of screening are as follows: Short-acting ESAs (EPO-alfa or equivalents)
• IV: Up to 9 doses; last EPO dose must be ≥2 days prior to start of screening
• SC: Up to 3 doses; last EPO dose must be ≥1 week (7 days) prior to start of screening
Darbepoetin
• IV: Up to 3 doses; last darbepoetin dose must be ≥1 week (7 days) prior to start of screening
• SC: Up to 2 doses; last darbepoetin dose must be ≥2 weeks (14 days) prior to start of screening
Continuous erythropoietin receptor activator (CERA) IV and SC
• IV or SC: Up to 2 doses; last CERA dose must be ≥2 weeks (14 days) prior to start of screening
2. Intravenous iron: there is no restriction regarding IV iron use during screening, provided it is administered in accordance with local standard of care.
3. Red blood cell transfusion within 4 weeks prior to randomization.
4. Active, clinically significant infection that could be manifested by white blood cell (WBC) count > ULN, and/or fever, in conjunction with clinical signs or symptoms of infection at the time of randomization.
5. History of chronic liver disease (eg, chronic infectious hepatitis, chronic auto-immune liver disease, cirrhosis, or fibrosis of the liver).
6. New York Heart Association Class III or IV congestive heart failure at screening.
7. Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event within a major vessel (excluding vascular dialysis access) (eg, deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
8. Uncontrolled hypertension, in the opinion of the Investigator, (eg, that requires a change in anti-hypertensive medication) within 2 weeks prior to randomization.
9. Renal imaging performed within 12 weeks prior to randomization indicative of a diagnosis or suspicion (eg, complex kidney cyst of Bosniak Category 2 or higher) of renal cell carcinoma.
10. History of malignancy, except for 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 disease that could impact erythropoiesis (eg, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) even if it is currently in remission.
13. Known, untreated proliferative diabetic retinopathy, diabetic macular edema, macular degeneration, or retinal vein occlusion (subjects who are already blind for the above reasons qualify to participate).
14. Known history of myelodysplastic syndrome or multiple myeloma.
15. Known hereditary hematologic disease such as thalassemia or sickle cell anemia, pure red cell aplasia, or other known causes for anemia other than CKD.
16. Known hemosiderosis, hemochromatosis, coagulation disorder, or a hypercoagulable condition.
17. Organ transplant: subjects with any of the following:
a. Experienced rejection of a transplanted organ within 6 months of transplantation
b. Currently on high doses of immunosuppressive therapy (per discretion of the Investigator)
c. Scheduled for organ transplantation. Note: being on a waiting list for kidney transplant is not exclusionary
18. Anticipated elective surgery, except for vascular access surgery or dialysis catheter placement, that is expected to lead to significant blood loss, or anticipated elective coronary revascularization.
19. Active or chronic gastrointestinal bleeding.
20. Any prior treatment with roxadustat or a HIF-PHI.
21. Use of iron-chelating agents within 4 weeks prior to randomization.
22. Known hypersensitivity reaction to any ESA.
23. Use of an investigational drug or treatment, participation in an investigational study, or presence of an expected carryover effect of an investigational treatment, within 4 weeks prior to randomization.
24. Anticipated use of dapsone or androgens at any dose amount or chronic use of acetaminophen or paracetamol > 2.0 g/day during the study.
25. History of alcohol or drug abuse within 6 months prior to randomization.
26. Females of childbearing potential, unless using contraception as detailed in the protocol; male subjects with sexual partners of childbearing potential who are not on birth control unless the male subject agrees to use contraception.
27. Pregnant or breastfeeding females.
28. Any medical condition that, in the opinion of the Investigator, may pose a safety risk to a subject in this study, may confound efficacy or safety assessment, or may interfere with study participation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of subjects who achieve a Hb response at two
consecutive visits during the first 24 weeks of treatment, without rescue
therapy within 6 weeks prior to the Hb response. This analysis is based
on the Per Protocol Set (PPS) population.
A Hb response is defined, using central laboratory values, as
- Hb ≥ 11.0 g/dL and a Hb increase from baseline by ≥ 1.0 g/dL in
subjects whose baseline Hb > 8.0 g/dL, or
- Increase in Hb ≥2.0 g/dL in subjects whose baseline Hb ≤ 8.0 g/dL. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After the first 24 weeks of treatment. |
|
| E.5.2 | Secondary end point(s) |
- Mean Hb change from baseline to the average level during the Evaluation Period, defined as Week 28 until Week 36 without rescue therapy within 6 weeks prior to and during the evaluation period. This analysis will be based on the PPS population.
- Average monthly IV iron use per subject during the Treatment Period.
- Mean change in low-density lipoprotein (LDL) cholesterol averaged over Weeks 12 to 24.
- Blood pressure effects:
- Proportion of subjects with exacerbation of hypertension, meeting at least one of the following criteria:
- Increase in BP: An increase from baseline of ≥ 20 mm Hg systolic BP and sBP >170 mmHg, or an increase from baseline of ≥ 15 mm Hg diastolic BP and dBP>100 mmHg. Increases from baseline in blood pressure must be confirmed by repeat measurement.
- Time to an increase in BP as defined above.
- Mean change in mean arterial pressure (MAP) averaged over Weeks 8 to 12.
- Time to achieve first Hb response as defined by the primary endpoint. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After completion of study and closure of data base. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| badanie z grupą kontrolną otrzymującą aktywne leczenie |
| study with active control arm |
|
| 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 | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Belarus |
| Brazil |
| Bulgaria |
| Chile |
| Colombia |
| Korea, Democratic People's Republic of |
| Latvia |
| Malaysia |
| Mexico |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Taiwan |
| Thailand |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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