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. |
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E.1.1.1 | Medical condition in easily understood language |
Anemia due to end-stage renal disease in incident-dialysis patients. |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054606 |
E.1.2 | Term | Secondary anemia |
E.1.2 | System Organ Class | 100000004851 |
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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 efficacy and safety of FG-4592 in the treatment of anemia in incident-dialysis subjects compared to Active Control. |
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E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy of FG-4592 in the maintenance of hemoglobin (Hb) compared to Active Control.
- Evaluate the utilization of intravenous (IV) iron with FG-4592 compared to Active Control.
- Evaluate effect of FG-4592 on serum lipid parameters compared to Active Control.
- Evaluate the effect of FG-4592 on blood pressure (BP) compared to Active Control.
- Evaluate time to achieve hemoglobin (Hb) response compared to Active Control.
- Evaluate health-related quality of life (HRQoL) benefit of FG-4592 |
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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 hemodialysis or peritoneal dialysis for native kidney end-stage renal disease (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
Peritoneal dialysis catheter in use.
5. Mean of the three most recent Hb values during the Screening Period, obtained at least 4 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 ≥50 ng/mL.
7. TSAT ≥10%.
8. Serum folate level, performed within 8 weeks prior to randomization ≥ lower limit of normal (LLN).
9. Serum vitamin B12 level, performed within 8 weeks prior to randomization ≥ LLN.
10. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3x upper limit of normal (ULN), and total bilirubin (Tbili)< 1.5 x ULN.
11. Body weight 45 to 160 kg (dry weight). |
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E.4 | Principal exclusion criteria |
1. Any ESA treatment within 12 weeks prior to randomization.
2. More than one dose of IV iron within 4 weeks prior to randomization.
3. RBC transfusion within 8 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.
5. History of chronic liver disease (e.g. 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.
7. Myocardial infarction, acute coronary syndrome, stroke, seizure, or a thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
8. Uncontrolled hypertension, in the opinion of the investigator, (e.g. that requires change in anti-hypertensive medication) within 2 weeks prior to randomization.
9. Renal ultrasound performed within 12 weeks prior to randomization indicative of a diagnosis or suspicion (e.g., complex kidney cyst of Bosniak Category II 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
(e.g., 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.
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 chronic kidney disease (CKD).
16. Known hemosiderosis, hemochromatosis, coagulation disorder, or a hypercoagulable condition.
17. Any prior organ transplant (that has not been explanted), or a scheduled organ transplantation.
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. Known, active or chronic gastrointestinal bleeding.
20. Any prior treatment with FG-4592 or a HIF prolyl hydroxylases (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 in any dose amount or chronic use of acetaminophen or paracetamol >2.0 g/day during the treatment or follow-up periods of the study.
25. History of alcohol or drug abuse within 2 years 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. |
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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.
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.
Rescue therapy for FG-4592 treated subjects is defined as ESA rescue or RBC transfusion, and rescue therapy for Epoetin alfa treated subjects is defined as RBC transfusion. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the first 24 weeks of treatment. |
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E.5.2 | Secondary end point(s) |
- Hemoglobin maintenance: Mean change in Hb averaged over 8 weeks of treatment at Weeks 28-36, without rescue therapy within 6 weeks prior to and during this 8-week evaluation period.
- Mean change in low-density lipoprotein (LDL) cholesterol averaged over Weeks 12-24.
- Average monthly IV iron use per subject during the Treatment Period.
- Blood pressure effects:
- Proportion of patients with exacerbation of hypertension, meeting at least one of the following criteria:
- increase in anti-hypertensive medication use,
- adverse event of hypertension, or
- increase in blood pressure: 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 blood pressure as defined in 3) above.
- Mean change in mean arterial pressure (MAP) averaged over Weeks 8-12.
- Time to achieve first Hb response as defined by the primary endpoint.
- Health related quality of life (HRQoL) will be assessed using the SF-36, vitality and physical functioning subscales. Both within treatment effect and between treatment effect will be assessed for Weeks 12, 28, and 52. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After completion of study and closure of data base. |
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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 | 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 |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |
Australia |
Estonia |
Latvia |
Lithuania |
Poland |
Romania |
Russian Federation |
United States |
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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 | 3 |
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 | 3 |
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 |