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.

Phase 2

Completed

Conditions: Anemia

Interventions: Biological: Sotatercept
Biological: Placebo

Registration Number: NCT01146574

Lead Sponsor: Celgene

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
0.3mg/kg Sotatercept	Sotatercept	Dose Group 1: 0.3 mg/kg sotatercept subcutaneous every 28 days
Placebo	Placebo	The Placebo to Sotatercept ratio is 1:3 meaning for every 1 patient that receives Placebo, 3 patients will receive Sotatercept.
0.1mg/kg Sotatercept	Sotatercept	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
0.5mg/kg Sotatercept	Sotatercept	Dose Group 2: 0.5 mg/kg sotatercept subcutaneous every 28 days
0.7mg/kg Sotatercept	Sotatercept	Dose Group 3: 0.7 mg/kg sotatercept subcutaneous every 28 days

Primary Outcome Measures

Name	Time	Method
AUCinf: Area Under the Concentration-time Curve From Time Zero Extrapolated to Infinity	From first dose up to Day 28	Area under the concentration-time curve from time zero extrapolated to infinity. Only Part 1 pharmacokinetic evaluable participants were pre-specified to be evaluated in this endpoint.
Apparent Total Clearance (CL/F)	From first dose up to Day 28	Apparent Total Clearance (CL/F) is defined as the volume of plasma from which the study drug is completely removed per unit of time. It is equal to the drug dose divided by the area-under-the-curve.
Apparent Volume of Distribution Based on Terminal Phase (Vz/F)	From first dose up to Day 28	Apparent volume of distribution based on terminal phase (Vz/F) is defined as the apparent volume in which the current amount of drug in the body must be dispersed in order to give the current plasma concentration. Apparent volume of distribution is important for determining the dose required to produce a desired plasma concentration of the drug.
Observed Maximum Concentration (Cmax)	From first dose up to Day 28	Cmax is a pharmacokinetic parameter defined as the observed maximum concentration of the study drug in the serum and/or blood. Cmax will be estimated from the sotatercept concentration versus time data using noncompartmental method.
Time to Maximum Concentration (Tmax)	From first dose up to Day 28	Time to observed maximum concentration (Tmax) is defined as the amount of time in days for a drug to reach the maximum concentration after administration.
Area Under Curve (AUC)-28 Days	From first dose up to Day 28	AUC-28 days is defined as area under the concentration-time curve over the first 28-day dosing interval
Terminal Half-Life (t1/2,z)	Days 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 22, 29, 43, 57, 85 and 113	Terminal plasma half-life (t1/2,z) is the time taken for concentration of the study drug to decrease from its maximum concentration (Cmax) to half of Cmax in the blood plasma.

Secondary Outcome Measures

Name	Time	Method
The Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)	From first dose up to 115 days post last dose	An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
Number of Participants With Hemoglobin > 12g/dL	Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309	Number of participants with hemoglobin \> 12g/dL including Hb values obtained after first study drug dose and before any rescue.
Blood Pressure Changes From Baseline	From pre-dose up to the final visit 112 days after last dose (up to 225 days)	Blood pressure was generally recorded on the day of dialysis and represent pre-dialysis values. Baseline is defined as blood pressure measurements recorded on Day 1 of the first dose administered.
Changes in Follicle Stimulating Hormone (FSH)	Day 1 (baseline), Day 15, Day 29, and Day 113	The change in follicle stimulating measured at pre-specified timepoints throughout the treatment period.
Number of Participants With Change From Baseline Hemoglobin ≥ 1g/dL	Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309	Number of participants with a change from in hemoglobin values ≥ 1g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Change From Baseline in Hemoglobin Values	From first dose up to Day 225	Dose Cycle 1 is defined as the first 28 days of treatment for Dose Groups 0.3 mg/kg, 0.5 mg/kg, and 0.7 mg/kg and the first 14 days of treatment for Dose Group 0.7/0.4 mg/kg. End of the Treatment Period is defined as the day before the follow-up phase started. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Proportion of Participants With Rise in Hemoglobin > 2 g/dL During 4 Week Period	Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309	Proportion of participants with rise in hemoglobin (Hb) \> 2 g/dL during a 4-week period including Hb values obtained after first study drug dose and before any rescue.
Number of Participants With Hemoglobin > 10g/dL and Change From Baseline Hemoglobin ≥ 1g/dL	Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309	Number of participants with Hemoglobin \> 10g/dL and a change from in hemoglobin values ≥ 1g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.
Length of Time to Rescue Therapy	From first dose up to blood transfusion or ESA therapy, up to approximately 209 days	The length of time in days that participants who were rescued received treatment. When applicable, participants were rescued for anemia. During the rescue, participants discontinued sotatercept and were unblinded to the study treatment. Participants who were rescued continued in the treatment phase of 200 days and a follow-up phase of 112 days after the treatment phase. Rescue is defined as the need for a blood transfusion or Erythropoiesis-stimulating agent (ESA) therapy.
Number of Participants With Hemoglobin > 10g/dL	Pre-dose; Dose 1-Days 1, 8, 15, 22, 29; Doses 2, 3, 4, 5, 6, 7-Days 1, 15, 29; Follow-up Phase Days 225, 253, 281, and 309	Number of participants with hemoglobin \> 10g/dL including Hb values obtained after first study drug dose and before any rescue. Baseline is defined as hemoglobin measurements recorded on Day 1 of the first dose administered.

Trial Locations

Locations (24): North American Research Institute
🇺🇸
Azusa, California, United States
Academic Medical Center
🇺🇸
Los Angeles, California, United States
Academic Medical Research Institute
🇺🇸
Los Angeles, California, United States
Pines Clinical Research Inc.
🇺🇸
Pembroke Pines, Florida, United States
Fresenius Medical Care North America MI
🇺🇸
Kalamazoo, Michigan, United States
Nephrology and Hypertension Associates, LTD
🇺🇸
Tupelo, Mississippi, United States
MetroHealth Medical Systems
🇺🇸
Cleveland, Ohio, United States
Corva Kidney Center Webster
🇺🇸
Houston, Texas, United States
Miracle Medical Clinic
🇺🇸
Houston, Texas, United States
Gessner Dialysis Center
🇺🇸
Houston, Texas, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Beechnut Dialysis Center
🇺🇸
Houston, Texas, United States
DaVita Clinical Research
🇺🇸
Minneapolis, Minnesota, United States
Kidney Specialists of Southen Nevada
🇺🇸
Las Vegas, Nevada, United States
Nephrology Associates, PC
🇺🇸
Nashville, Tennessee, United States
West Glendale Dialysis
🇺🇸
Glendale, California, United States
Nephrology Specialist Medical Group
🇺🇸
Orange, California, United States
California Institute of Renal Research
🇺🇸
La Mesa, California, United States
University of Kentucky
🇺🇸
Lexington, Kentucky, United States
St. Louis University Medical Center
🇺🇸
Saint Louis, Missouri, United States
Brookview Hill Research Associates, LLC
🇺🇸
Winston-Salem, North Carolina, United States
Northeast Clinical Research Center
🇺🇸
Bethlehem, Pennsylvania, United States
Tyler Nephrology Associates, PC
🇺🇸
Tyler, Texas, United States
University of Virginia at University Ave.
🇺🇸
Charlottesville, Virginia, United States