| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| End-stage kidney disease (ESKD) who are on hemodialysis and will be switched from their current stable treatment with erythropoiesisstimulating agent (ESA) to sotatercept. |
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| E.1.1.1 | Medical condition in easily understood language |
Anemia due to kidney disease in people on hemodialysis
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| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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 |
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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 |
Part 1
To determine the multiple dose pharmacokinetics, safety, and tolerability of IV and SQ dosing of sotatercept administered at each dose level.
Part 2
To determine the safety and efficacy of the selected starting dose(s), route(s) of administration, and dose modification regimen(s) on maintenance of hemoglobin concentrations between baseline and the Evaluation Phase |
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| E.2.2 | Secondary objectives of the trial |
Part 1
•To determine hemoglobin response at different dose levels
•To determine pharmacodynamic (hemoglobin) relationship between IV and SQ doses of sotatercept at different dose levels
•To select a starting dose(s) and route(s) of administration for switching subjects from ESA for Part 2
Part 2
•To determine the effect of sotatercept on bone mineral density (BMD)
•Other secondary objectives are:
-To determine the safety and efficacy of the selected starting dose(s), route(s) of administration, and dose modification regimen(s) on maintenance of hemoglobin concentrations from baseline through the end of the Maintenance Phase
-To determine hemoglobin response during the Evaluation Phase and end of the Maintenance Phase
-To determine the pharmacodynamic effects on parameters of : Mineral metabolism,Erythropoietin,Bone histology,Vascular calcification,Iron metabolism
To determine the multiple dose pharmacokinetics of sotatercept at the selected dose(s)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Males or females ≥ 18 years of age at the time of signing informed consent document.
2.Clinically stable in the judgment of the investigator.
3.Subjects on at least 6 hours of hemodialysis per week, for at least 12 weeks before screening and during the study.
4.Subjects must be on a stable IV or SQ dose of ESA (excluding methoxy polyethylene glycol epoetin-beta) to maintain hemoglobin. A stable dose is defined as ≤ 50% change from the maximum prescribed weekly ESA dose ([max-min]/max ≤ 0.5) and no change in frequency during the last 6 weeks prior to randomization unless the dose is held for high hemoglobin. If ESA dose is held for high hemoglobin, subject must be restarted on a stable dose (defined as ≤ 50% change from prior dose). Maximum allowed ESA dose must be equivalent to epoetin ≤ 500 IU/kg/week, or darbepoetin ≤ 95 mcg/week.
5.A mean hemoglobin concentration ≥ 10 to ≤ 12 g/dL (≥ 100 to ≤ 120 g/L) obtained from three consecutive (each done on different days) predialysis hemoglobin concentrations, with the last hemoglobin concentration done within the 7 days prior to randomization (if local laboratory values are used, they should be obtained consistently from the same laboratory).
6.Subjects must have adequate iron status defined as one transferrin saturation ≥ 20% prior to randomization.
7.A Kt/V ≥ 1.2 or urea reduction ratio ≥ 65% at screening, (historical values within 1 month prior to screening are acceptable).
8.The subject has one PTH concentration ≤ 1000 pg/mL, one phosphorus concentration ≤ 7 mg/dL, one total albumin-corrected calcium concentration > 8.0 mg/dL to < 10.5 mg/dL , and one magnesium concentration ≥ 1.5 mEq/L prior to randomization.
9.A BMI value ≥ 18.5 kg/m2 at screening. Weight at screening will be collected postdialysis (dry weight) for BMI calculation.
10.Female subjects of childbearing potential participating in the study are to use highly effective methods of birth control during study participation. Females of childbearing potential must have a negative serum pregnancy test prior to randomization. In addition, subjects must be educated concerning measures to be used to prevent pregnancy and potential toxicities. (A female of childbearing potential is a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy; or who has not been postmenopausal for at least 24 consecutive months ie, who has had menses at some time in the preceding 24 months).
Some highly effective methods of birth control include:
•Oral contraceptives, intrauterine device, tubal ligation or vasectomized partner
OR
•Two forms of barrier method birth control, e.g., a latex condom PLUS a diaphragm with spermicide OR a latex condom PLUS a contraceptive sponge with spermicide. If a non-latex condom is used, it cannot be made out of natural (animal) membrane
11.Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or non latex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while participating in the study.
12.Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
13.Able to adhere to the study visit schedule and comply with all protocol requirements.
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| E.4 | Principal exclusion criteria |
1. Non renal causes of anemia due to active inflammatory disease such as systemic lupus erythematosus, active liver disease, hypersplenism, gastrointestinal bleeding, osteomyelitis, tuberculosis, lung abscess, etc.
2. Subjects on peritoneal dialysis.
3. Systemic hematological disease such as sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma, hemolytic anemia.
4. High sensitivity C-reactive protein > 50 mg/L at screening.
5. Subject has alanine transaminase (ALT) or aspartate transaminase (AST) laboratory
values > 2 times the upper limit of normal (ULN) at screening.
6. Uncontrolled diabetes mellitus (HbA1c > 9) at screening.
7. Uncontrolled hypertension defined as mean of home systolic blood pressure > 160 mm Hg or mean of home diastolic blood pressure > 90 mm Hg calculated once during the screening period prior to randomization (A mean of 4 consecutive days of home systolic and diastolic blood pressure values taken during a 7-day window in the screening period prior to randomization, with a minimum of 6 values for calculating the mean are required - 3 taken from a single morning set of measurements, and 3 taken from a single evening set of measurements. Note: Both the mean systolic and diastolic home blood pressure eligibility must be met).
8. Subjects with heart failure as classified by the New York Heart Association (NYHA) classification of 3 or higher, (see Appendix E).
9. Compromised venous access for the purpose of hemodialysis or obtaining blood samples for the study.
10. Subjects taking high dose vitamin D or calcimimetic medications (such as cinacalcet ≥ 120 mg once daily; paricalcitol 0.24 mcg/kg three times weekly; doxercalciferol 6 mcg three times weekly) within 3 months prior to screening and during the course of the study.
11. Subjects taking drugs that affect bone turnover (see prohibited concomitant therapy Section 9.2) within 3 months prior to screening and during the course of the study.
12. ESKD due to malignancy.
13. History of malignancy (except excised and cured non-melanoma skin cancer, or cervical carcinoma in situ that was surgically ablated more than 1 year ago).
14. Active serious infection or history of a recurrent serious infection that is likely to recur during the study, with the last infection within 3 months prior to the screening visit (immunosuppressants and high dose corticosteroids are excluded eg, prednisone ≥ 10 mg per day or equivalent, see Section 9.2).
15. Subject has human immunodeficiency virus (HIV).
16. Major surgeries or surgeries (excludes vascular access surgery) requiring hospitalization within 28 days prior to randomization and/or expected during the course of the study (subjects must have, in the judgment of the investigator, completely recovered from any previous surgery prior to randomization).
17. Anticipated or scheduled living donor renal transplant during the course of the study.
18. Any RBC transfusions within 8 weeks prior to screening.
19. Life expectancy < 1 year.
20. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product or to the specific iron products needed to normalize iron levels for subjects or to tetracycline (or appropriate substitute) for subjects who consent to bone biopsy.
21. Subjects who received treatment with another investigational drug or device within 28 days prior to randomization, or if the half-life of the previous product is known, within 5 times the half life prior to dosing, whichever may be longer.
22. Pregnant or breast feeding females.
23. Any significant medical condition, laboratory abnormality, or psychiatric illness which in the judgment of the investigator places the subject at unacceptable risk if he/she were to participate in the study (subjects who consent to bone biopsies should be evaluated for routine pre-operative examination). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
•Pharmacokinetic parameters, including Observed maximum concentration (Cmax), Time to Cmax (Tmax), Area under the concentration-time curve over the 28-day dosing interval (AUC28d), Terminal half-life (t1/2,z)
Part 2
•Change in mean hemoglobin concentration between baseline and the Evaluation Phase (baseline hemoglobin value is mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration done within the 7 days prior to randomization and the value obtained on the day of randomization. The Evaluation Phase hemoglobin value is mean of hemoglobin concentrations from Day 176 to Day 197 [Visit 16 to 19])
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
as specified in Section E.5.1
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| E.5.2 | Secondary end point(s) |
Part 1
•Proportion of subjects able to maintain a mean (Visit 14 to 17) hemoglobin concentration ≥ 10 to ≤ 12 g/dL without the need for rescue at each dose level (mean hemoglobin value is a mean of hemoglobin concentrations from Day 99 [Visit 14] to Day 113 [Visit 17])
•Change in mean hemoglobin concentration between baseline and Visit 14 to 17 at each dose level (baseline hemoglobin value is mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration done within the 7 days prior to randomization and the value obtained on the day of randomization. Visit 14 to 17 hemoglobin value is a mean of hemoglobin concentrations from Day 99 [Visit 14] to Day 113 [Visit 17]))
Part 2
•The key secondary endpoint is the percent change in volumetric bone mineral density (vBMD) from baseline measured by quantitative computed tomography (QCT) at Day 393 (Visit 26)
Other Secondary Endpoints:
•Change in mean hemoglobin concentration between baseline and the end of the Maintenance Phase (baseline hemoglobin value is mean of three consecutive hemoglobin concentrations with the last hemoglobin concentration done within the 7 days prior to randomization and the value obtained on the day of randomization. Maintenance Phase hemoglobin value is mean of hemoglobin concentrations from Day 365 to Day 393 [Visit 25 to 26])
•Proportion of subjects able to maintain a mean (Visit 16 to 19) hemoglobin concentration ≥ 10 to ≤ 12 g/dL without the need for rescue during the Evaluation Phase (Evaluation Phase hemoglobin value is mean hemoglobin concentrations from Day 176 to Day 197 [Visit 16 to 19]) and the Maintenance Phase (Maintenance Phase hemoglobin value is mean of hemoglobin concentrations from Day 365 to Day 393 [Visit 25 to 26])
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
as specified in Section E.5.2
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| ESA dose as per subject's regimen during screening (IV or SQ) |
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| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 6 |
| 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 | 6 |
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