A Phase 2a Study To Evaluate The Pharmacokinetics, Safety, Efficacy, Tolerability, And Pharmacodynamics of Sotatercept (ACE-011) for the Correction of Anemia in Subjects With End-stage Renal Disease on Hemodialysis.

Study Overview
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Brief Summary
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This is the first study in hemodialysis subjects with anemia to evaluate the pharmacokinetics, safety, efficacy, tolerability, and pharmacodynamics of sotatercept (ACE-011)

Detailed Description
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Part 1: Approximately 8 subjects will be randomized to receive either a single 0.1 mg/kg subcutaneous dose of sotatercept or matching placebo in a 3:1 ratio Part 2: Approximately 8 subjects will be randomized to each of the 3 sequential dose groups (0.3mg/kg or 0.5mg/kg or 0.7 mg/kg) with a 3:1 ratio of sotatercept or placebo (6 subjects in the sotatercept arm and 2 in the placebo arm). A total of 24-36 subjects may be randomized in the 3 dose groups.

Official Title
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A Phase 2a, Multi-center, Randomized, Single Dose, Double-blind, Placebo-controlled Followed by a Multiple-dose, Single-blind, Placebo-controlled, Dose Escalation Study to Evaluate the Pharmacokinetics, Safety, Efficacy, Tolerability, and Pharmacodynamics of Sotatercept (ACE-011) for the Correction of Anemia in Subjects With End-stage Renal Disease (ESRD) on Hemodialysis (HD).

Conditions
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Anemia

Intervention / Treatment
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* Biological: Sotatercept
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥18 years of age. Subjects on hemodialysis for at least 12 weeks before screening Subjects on a stable dose of Erythrocyte Stimulating Agents product to maintain Hemoglobin (Hb) for at least 6 weeks prior to screening. 3 consecutive pre-dialysis Hb concentrations with a mean ≥10 to ≤ 12 g/dL (≥100 to ≤120 g/L) at screening and one pre-dialysis Hb concentration ≥8 to < 10 g/dL (≥ 80 to < 100 g/L) before randomization. Adequate iron status defined as serum transferrin saturation ≥ 20% before randomization. Exclusion Criteria: Non renal causes of anemia. Subjects on peritoneal dialysis. Systemic hematological disease High sensitivity C-reactive protein >50mg/L at screening. Alanine transaminase (ALT) or aspartate transaminase (AST) laboratory values > 2 times the upper limit of normal (ULN) at screening. Uncontrolled diabetes mellitus (HbA1c > 9) at screening. Uncontrolled hypertension. Red Blood Count (RBC) transfusions within 8 weeks prior to screening. Active serious infection or history of recurrent serious infection likely to recur during the study History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product or to the iron products needed to normalize iron levels for subjects. Subjects that received treatment with another investigational drug or device within 28 days prior to Day 1 Pregnant or lactating females.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.1mg/kg Sotatercept<br>Approximately 8 subjects will be randomized to receive either a single 0.1 mg/kg subcutaneous dose of sotatercept or matching placebo in a 3:1 ratio | Biological: Sotatercept<br>* Part 1: Sotatercept single dose 0.1mg/kg subcutaneous Part 2: Sotatercept starting dose groups of 0.3mg/kg, 0.5mg/kg or 0.7 mg/kg in a sequential design, dosed subcutaneously every 28 days for up to 8 doses<br>* Other names: ACE-011;|
| Experimental: 0.3mg/kg Sotatercept<br>Dose Group 1: 0.3 mg/kg sotatercept subcutaneous every 28 days | Biological: Sotatercept<br>* Part 1: Sotatercept single dose 0.1mg/kg subcutaneous Part 2: Sotatercept starting dose groups of 0.3mg/kg, 0.5mg/kg or 0.7 mg/kg in a sequential design, dosed subcutaneously every 28 days for up to 8 doses<br>* Other names: ACE-011;|
| Experimental: 0.5mg/kg Sotatercept<br>Dose Group 2: 0.5 mg/kg sotatercept subcutaneous every 28 days | Biological: Sotatercept<br>* Part 1: Sotatercept single dose 0.1mg/kg subcutaneous Part 2: Sotatercept starting dose groups of 0.3mg/kg, 0.5mg/kg or 0.7 mg/kg in a sequential design, dosed subcutaneously every 28 days for up to 8 doses<br>* Other names: ACE-011;|
| Experimental: 0.7mg/kg Sotatercept<br>Dose Group 3: 0.7 mg/kg sotatercept subcutaneous every 28 days | Biological: Sotatercept<br>* Part 1: Sotatercept single dose 0.1mg/kg subcutaneous Part 2: Sotatercept starting dose groups of 0.3mg/kg, 0.5mg/kg or 0.7 mg/kg in a sequential design, dosed subcutaneously every 28 days for up to 8 doses<br>* Other names: ACE-011;|
| Placebo Comparator: Placebo<br>The Placebo to Sotatercept ratio is 1:3 meaning for every 1 patient that receives Placebo, 3 patients will receive Sotatercept. | Biological: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK-Observed maximum Concentration (Cmax) | PK-Observed maximum Concentration (Cmax) | Up to 309 days | 
| PK-Time to maximum concentration (Tmax) | PK-Time to maximum concentration (Tmax) | Up to 309 days | 
| PK-Area under the concentration-time curve over the 28 day dosing interval (AUC 28d) | PK-Area under the concentration-time curve over the 28 day dosing interval (AUC 28d) | Up to 309 days | 
| PK-Terminal half-life (T1/2,z) | PK-Terminal half-life (T1/2,z) | Up to 309 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events | Number of participants with Adverse Events | Up to 309 days | 
| Proportion of subjects with Hb > 12g/dL | Proportion of subjects with Hb > 12g/dL | Up to 309 days | 
| Proportion of subjects with rise in Hb > 2 g/dL during a 4 week period | Proportion of subjects with rise in Hb > 2 g/dL during a 4 week period | Up to 309 days | 
| Frequency of clinically significant changes in laboratory parameters from baseline | Frequency of clinically significant changes in laboratory parameters from baseline | Up to 309 days | 
| Blood pressure changes from baseline | Blood pressure changes from baseline | Up to 309 days | 
| Proportion of subjects that are able to achieve an absolute Hb concentration of > 10 g/dL | Proportion of subjects that are able to achieve an absolute Hb concentration of > 10 g/dL | Up to 309 days | 
| Time to reach target Hb concentration (> 10 g/dL) and target increase in Hb (≥ 1g/dL) | Time to reach target Hb concentration (> 10 g/dL) and target increase in Hb (≥ 1g/dL) | Up to 309 days | 
| Proportion of subjects rescued and length of time to rescue therapy | Proportion of subjects rescued and length of time to rescue therapy | Up to 309 days | 
| Changes in Follicle Stimulating Hormone (FSH) and Sex Steroid Concentrations | Changes in Follicle Stimulating Hormone and Sex Steroid Concentrations | Up to 309 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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End-Stage Renal Disease, Anemia, Hemodialysis, Renal Anemia, ESRD