| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anemia of Chronic kidney disease (CKD) |
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| E.1.1.1 | Medical condition in easily understood language |
| Decrease of hemoglobin in the blood of patients suffering from kidney disease who require dialysis |
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| 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 | 10002272 |
| E.1.2 | Term | Anemia |
| E.1.2 | System Organ Class | 100000004851 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076412 |
| E.1.2 | Term | Chronic kidney disease stage 5 |
| E.1.2 | System Organ Class | 100000004857 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076411 |
| E.1.2 | Term | Chronic kidney disease stage 4 |
| E.1.2 | System Organ Class | 100000004857 |
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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 |
| The primary objective of the trial is to demonstrate the efficacy and safety of vadadustat compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis subjects after conversion from current ESA therapy. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| optional pharmacogenomic (PGx) sub-study |
|
| E.3 | Principal inclusion criteria |
1) ≥ 18 years of age.
2) Receiving chronic, outpatient TIW in-center hemodialysis for end-stage renal disease for at least 12 weeks prior to Screening.
3) Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥ 1.2 using the most recent historical measurement within 8 weeks prior to or during Screening.
4) Use of any approved ESA for at least the 8 weeks prior to Screening Visit 2.
5) Two Hb values, at least 4 days apart, measured by the central laboratory during Screening within the following prespecified ranges:
a) Hb values between 8.0 and 11.0 g/dL (inclusive) in the US.
b) Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe.
6) Serum ferritin ≥ 100 ng/mL and TSAT ≥ 20% during Screening.
7) Folate and vitamin B12 measurements ≥ lower limit of normal during Screening.
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| E.4 | Principal exclusion criteria |
1) Women of childbearing potential (WOCBP) who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of investigational medicinal product (IMP). If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, or birth control (Section 10.3 of protocol).
2) Male subjects who have not had a vasectomy and do not agree to the following: use of an acceptable form of contraception during the study (see Section 10.3) and for 30 days after the last dose of the study drug; to not donate semen during the study and for at least 30 days after the last dose of vadadustat.
3) Women who are breast feeding and/or who have a positive pregnancy test result prior to receiving IMP.
4) Subjects with contraindication to required trial assessment.
5) Subjects who, is in opinion of the investigator or medical monitor, have a medical history or medical findings inconsistent with safety or trial compliance.
6) Anemia due to a cause other than CKD (eg, sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia).
7) Subjects meeting cut-off of the following equivalent mean weekly doses calculated over 8 weeks prior to Screening Visit 2:
a) Methoxy polyethylene glycol-epoetin beta > 50 µg/week.
b) Darbepoetin alfa > 100 µg/week.
c) Epoetin analogues > 23000 IU/week.
8) Active bleeding or recent blood loss within 8 weeks prior to randomization.
9) Red blood cell transfusion within 8 weeks prior to randomization.
10) Anticipated to discontinue hemodialysis during the trial.
11) Judged by the investigator that the subject is likely to need rescue therapy (ESA administration or RBC transfusion) immediately after enrollment in the trial.
12) History of chronic liver disease (eg, chronic infectious hepatitis, chronic autoimmune liver disease, cirrhosis or fibrosis of the liver).
13) Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin > 1.5 x upper limit of normal (ULN) during Screening. Subjects with a history of Gilbert’s syndrome are not excluded.
14) Current uncontrolled hypertension as determined by the investigator that would contraindicate the use of an ESA.
15) Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), surgical or percutaneous intervention for coronary, cerebrovascular or peripheral artery disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, sustained ventricular tachycardia, hospitalization for HF or New York Heart Association Class IV HF, or stroke within 12 weeks prior to or during Screening.
16) History of new or recurrent malignancy within 2 years prior to and during Screening or currently receiving treatment or suppressive therapy for cancer. Subjects with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical carcinoma in situ are not excluded.
17) History of a new or recurrent episode of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during Screening.
18) History of hemosiderosis or hemochromatosis.
19) History of prior organ transplantation (subjects with a history of failed kidney transplant or corneal transplants are not excluded).
20) Scheduled organ transplant from a living donor and subjects on the kidney transplant wait-list who are expected to receive a transplant within 6 months.
21) History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for knee arthritis is not excluded).
22) Known hypersensitivity to vadadustat, darbepoetin alfa, or any of their excipients.
23) Use of an investigational medication within 30 days or 5 half-lives of the investigational medication (whichever is longer), prior to screening or during screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase inhibitor. Subjects may participate in another concurrent trial only if that trial is a non-interventional, observational investigation.
24) Subjects with bilateral native nephrectomy.
25) Treated with probenecid within the 28-day Screening Period prior to randomization or during the study treatment duration.
26) Any other reason, which in the opinion of the investigator, would make the subject not suitable for participation in the trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| efficacy endpoints: change in hemoglobin (Hb) between Baseline (average pretreatment Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, inclusive). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| efficacy endpoints: change in Hb value between Baseline and the secondary evaluation period (average Hb from Weeks 46 to 52). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| 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 | 3 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Belgium |
| Czech Republic |
| Hungary |
| Italy |
| Poland |
| Spain |
| United States |
|
| 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
|
The end of trial date is defined as the last date of contact or the date of final contact
attempt from the safety follow-up electronic case report form (eCRF) page for the last
subject completing or withdrawing from the trial.
The trial will be considered completed (end of trial) after all randomized subjects have
completed their final trial visit (ET, Week 52/EOT, or Safety Follow-Up). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 5 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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