A Phase 2 Study of Intravenous or Subcutaneous Dosing of Sotatercept (ACE-011) in Patients With End-Stage Kidney Disease on Hemodialysis

A Phase 2 Multicenter, Randomized, Open-Label , Multiple-Dose Study of Intravenous and Subcutaneous Administration of Sotatercept (ACE-011) in Subjects With End-Stage Kidney Disease on Hemodialysis Switched From Erythropoeisis Stimulating Agents With Staggered Dose Group Escalation in Part 1 Followed by a Parallel Group, Active Controlled Study of Selected Dose(s) and Regimen(s) in Part 2: To Evaluate the Pharmacokinetics, Safety, Tolerability, Efficacy, Dosing Regimen, and Pharmacodynamics of Sotatercept

To determine the optimal route of administration, dose level, and safety of intravenous and subcutaneous dosing of sotatercept for maintaining hemoglobin levels in subjects who are on hemodialysis.

Study Overview

• Status: Completed
• Conditions: Anemia; Kidney Failure, Chronic
• Intervention / Treatment: Biological: Sotatercept; Biological: Sotatercept

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Baudour, Belgium, 7331
    • Centre Hospitalier EpiCURA - Clinique Louis Caty de Baudour
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg
  • Liege, Belgium, 4000
    • CHR de la Citadelle
• Germany
  • Coburg, Germany, 96450
    • KfH Nierenzentrum Coburg
  • Düsseldorf, Germany, 40210
    • Gemeinschaftspraxis und Dialysezentrum Karlstrass
  • München, Germany, 80337
    • KfH Kuratorium für Dialyse und Nierentransplantation e.V.
  • Rosenheim, Germany, 83022
    • KfH Nierenzentrum Rosenheim
• Portugal
  • Faro, Portugal, 8000
    • Nephrocare Faro
  • Lisboa, Portugal, 1649-035
    • Hospital de Santa Maria
  • Portimão, Portugal, 8500-311
    • Nephrocare Portimao
• Spain
  • Almeria, Spain, 04009
    • Complejo Hospitalario de Torrecardenas
  • Barcelona, Spain, 08036
    • Hospital Clinic of Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Galdakao, Spain, 48960
    • Hospital Galdakao-Usansolo
  • Madrid, Spain, 28041
    • Hospital 12 De Octubre
  • Madrid, Spain, 28007
    • Servicio de Nefrologia Hospital General Universitario Gregorio Maranon
  • Majadahonda, Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Santander, Cantabria, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Torrevieja (Alicante), Spain, 03186
    • Hospital de Torrevieja
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Trust
  • Glasgow, United Kingdom, G11 6NT
    • Glasgow Royal Infirmary
  • London, United Kingdom, SW17 0QT
    • St Georges Healthcare NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males or females ≥ 18 years of age.
2. Subjects on at least 6 hours of hemodialysis per week, for at least 12 weeks before screening
3. Subjects must be on a stable intravenous or subcutaneous dose of Erythropoietin Stimulating Agents (excluding methoxy polyethylene glycol-epoetin beta [Mircera]) to maintain hemoglobin.
4. A mean predialysis hemoglobin concentration ≥ 10 g/dL (grams per deciliter) to ≤ 12 g/dL (≥ 100 g/L (grams per liter) to ≤ 120 g/L) obtained from three consecutive days.

4. A Body Mass Index value ≥ 18.5 kg/m2 (kilograms per m2) at screening. 5. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.

6. Able to adhere to the study visit schedule and comply with all protocol requirements.

Exclusion Criteria:

1. Non renal causes of anemia
2. Subjects on peritoneal dialysis.
3. Systemic hematological disease
4. Uncontrolled diabetes mellitus (HbA1c (hemoglobin A1c) > 9%) at screening.
5. Uncontrolled hypertension defined as mean of home systolic blood pressure > 160 mm Hg (millimeter of mercury) or mean of home diastolic blood pressure > 90 mm Hg calculated once during the screening period prior to randomization
6. Subjects with heart failure
7. History of malignancy (except excised and cured non-melanoma skin cancer, or cervical carcinoma in situ that was surgically ablated more than 5 years ago).
8. Anticipated or scheduled living donor renal transplant during the course of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous Dose Group 1, 2, and 3; Intravenous Dose Group 1 starting at 0.1 mg/kg and escalated in Dose Groups 2 (0.2 mg/kg) and Dose Group 3 (0.1, 0.2, 0.3, 0.4 mg/kg, titrated based on titration rules, administered every 14 days)	Biological: Sotatercept; Sotatercept is dosed intravenously every 14 days. The dose a subject receives will depend on the randomization arm and the dose group.; Other Names: ACE-011; Biological: Sotatercept; Sotatercept is dosed subcutaneously every 14 days. The dose a subject receives will depend on the randomization arm and the dose group.; Other Names: ACE-011
Experimental: Subcutaneous Dose Group 1, 2, and 3; Subcutaneous Dose Group 1 starting at 0.13 mg/kg and escalated in Dose Groups 2 (0.26 mg/kg) and Dose Group 3 (0.4 to 0.5 mg/kg, titrated based on titration rules, administered every14 days)	Biological: Sotatercept; Sotatercept is dosed intravenously every 14 days. The dose a subject receives will depend on the randomization arm and the dose group.; Other Names: ACE-011; Biological: Sotatercept; Sotatercept is dosed subcutaneously every 14 days. The dose a subject receives will depend on the randomization arm and the dose group.; Other Names: ACE-011

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Serum Concentration-Time Curve Over Dosing Interval (AUC14d) (14 Days)	Area Under the plasma concentration-time curve over 14-day dosing interval (AUC14) for Sotatercept., The PK population included all participants in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Doses 1-2: predose and postdose at 5 min (IV only) 4 hours, 3, and 7 days after each dose; Doses 3-7: predose, and postdose at 5 min after IV injection after each dose; Final dose: predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14 days after dose
Area Under the Serum Concentration- Time Curve Over From Day 1 to Day 28 (AUC28d)	Area under the plasma concentration-time curve over 28-day dosing interval (AUC28d). All analyses of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Doses 1-2: predose and postdose at 5 min (IV only) 4 hours, 3, and 7 days after each dose; Doses 3-7: predose, and postdose at 5 min after IV injection after each dose; Final dose: predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14 days after dose
Maximum Observed Serum Concentration Obtained From the First Dose (Cmax14d)	Maximum observed serum concentration (Cmax14d) of sotatercept, obtained directly from the observed concentration-time data. The PK population included all participants in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Doses 1-2: predose and postdose at 5 min (IV only) 4 hours, 3, and 7 days after each dose; Doses 3-7: predose, and postdose at 5 min after IV injection after each dose; Final dose: predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14 days after dose
Maximum Observed Serum Concentration (Cmax28d) Obtained From the Combined First 2 Doses	Maximum observed serum concentration (Cmax28d) of sotatercept, obtained directly from the observed concentration-time data combining the profiles following the first two doses. The PK population included all participants in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Doses 1-2: predose and postdose at 5 min (IV only) 4 hours, 3, and 7 days after each dose; Doses 3-7: predose, and postdose at 5 min after IV injection after each dose; Final dose: predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14 days after dose
Time to Reach Maximum Observed Serum Concentration (Tmax)	Time to maximum serum concentration (Tmax) of sotatercept, obtained directly from the observed concentration-time data. The PK population included all participants in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Doses 1-2: pre- and postdose at 5 min (IV only) 4 hrs, 3, and 7 days after each dose; Doses 3-7: pre-, and postdose at 5 min after IV injection after each dose; Final dose: pre- and postdose at 5 min (IV only), 4 hrs, 3, 7, 14, 28, 56, 84, and 112 days
Estimate of Terminal Elimination Half-Life in Serum at Final Dose Only (t1/2)	Terminal elimination half-life (T1/2). The PK population included all participants in the safety population with at least one non-missing plasma concentration data. All analyses of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14, 28, 56, 84, and 112 days after the final dose.
Lambda (ʎz): Apparent Terminal Rate Constant (at Final Dose Only)	Lambda, apparent terminal rate constant (final dose only). The PK population included all participants in the safety population with at least one non-missing plasma concentration data. All analysis of PK data were based on the PK population and participants were analyzed according to the treatment group to which they were randomized.	Predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14, 28, 56, 84, and 112 days after the final dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Mean Hemoglobin ≥ 100 g/L to ≤ 120 g/L Without Rescue Medication	The percentage of participants able to maintain a mean (Visit 14 to 17) hemoglobin concentration ≥ 100 g/L to ≤ 120 g/L without the need for rescue medication at each dose level. Mean hemoglobin value is a mean of hemoglobin concentrations from Visit 14 to Visit 17 (days 99 to 113).	Visit 14 to Visit 17 (days 99 to 113)
Change From Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (All Participants Regardless of Rescue)	Change in mean hemoglobin concentration between baseline and Visit 14 to 17 at each dose level. Baseline hemoglobin value is the 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].	Baseline and Visit 14 to Visit 17 (days 99 to 113)
Change From Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (Participants Not Rescued Prior to Day 115)	Change in mean hemoglobin concentration between baseline and Visit 14 to 17 at each dose level for participants not rescued prior to Day 115. Baseline hemoglobin value is the 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].	Baseline and Visit 14 to Visit 17 (days 99 to 113)
Number of Participants With Adverse Events (AEs)	Treatment-emergent adverse event (TEAE) was defined as an adverse event with start date on or after date of first dose of study drug. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participants during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. A serious adverse event is defined as any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. Severity and intensity was assessed using the following grading scale: Mild, Moderate and Severe (could be non-serious or serious).	From date of first dose of investigational product to 112 days after the last dose or until the last study visit, whichever period was longer. The maximum duration for any IV or SC dose was 114 days. Up to approximately 226 days.

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: William Smith, MD, Celgene Corporation

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2013
• Primary Completion (Actual): August 31, 2016
• Study Completion (Actual): August 31, 2016

Study Registration Dates

• First Submitted: November 26, 2013
• First Submitted That Met QC Criteria: November 26, 2013
• First Posted (Estimated): December 3, 2013

Study Record Updates

• Last Update Posted (Actual): June 24, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Anemia; Chronic Kidney Disease; Dialysis; End Stage Kidney Disease; Erythrpoietin Stimulating Agent (ESA)
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Renal Insufficiency, Chronic; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Kidney Failure, Chronic; Renal Insufficiency
• Other Study ID Numbers: ACE-011-REN-002; 2012-003788-23 (EudraCT Number)