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

Phase 2

Completed

Conditions: Anemia
Kidney Failure, Chronic

Interventions: Biological: Sotatercept

Registration Number: NCT01999582

Lead Sponsor: Celgene

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

Males or females ≥ 18 years of age.
Subjects on at least 6 hours of hemodialysis per week, for at least 12 weeks before screening
Subjects must be on a stable intravenous or subcutaneous dose of Erythropoietin Stimulating Agents (excluding methoxy polyethylene glycol-epoetin beta [Mircera]) to maintain hemoglobin.
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.
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.
Able to adhere to the study visit schedule and comply with all protocol requirements.

Exclusion Criteria

Non renal causes of anemia
Subjects on peritoneal dialysis.
Systemic hematological disease
Uncontrolled diabetes mellitus (HbA1c (hemoglobin A1c) > 9%) at screening.
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
Subjects with heart failure
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).
Anticipated or scheduled living donor renal transplant during the course of the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intravenous Dose Group 1, 2, and 3	Sotatercept	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)
Subcutaneous Dose Group 1, 2, and 3	Sotatercept	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)

Primary Outcome Measures

Name	Time	Method
Estimate of Terminal Elimination Half-Life in Serum at Final Dose Only (t1/2)	Predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14, 28, 56, 84, and 112 days after the final dose.	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.
Maximum Observed Serum Concentration Obtained From the First Dose (Cmax14d)	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 (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.
Area Under the Serum Concentration-Time Curve Over Dosing Interval (AUC14d) (14 Days)	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 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.
Maximum Observed Serum Concentration (Cmax28d) Obtained From the Combined First 2 Doses	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) 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.
Time to Reach Maximum Observed Serum Concentration (Tmax)	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	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.
Lambda (ʎz): Apparent Terminal Rate Constant (at Final Dose Only)	Predose and postdose at 5 min (IV only) 4 hours, 3, 7, 14, 28, 56, 84, and 112 days after the final dose	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.
Area Under the Serum Concentration- Time Curve Over From Day 1 to Day 28 (AUC28d)	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 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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Mean Hemoglobin ≥ 100 g/L to ≤ 120 g/L Without Rescue Medication	Visit 14 to Visit 17 (days 99 to 113)	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).
Change From Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (All Participants Regardless of Rescue)	Baseline and Visit 14 to Visit 17 (days 99 to 113)	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 \[Visit 17\].
Change From Baseline in Mean Hemoglobin Concentration for Visit 14 to 17 (Participants Not Rescued Prior to Day 115)	Baseline and Visit 14 to Visit 17 (days 99 to 113)	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 \[Visit 17\].
Number of Participants With Adverse Events (AEs)	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.	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).

Trial Locations

Locations (23): KfH Kuratorium für Dialyse und Nierentransplantation e.v.
🇩🇪
München, Germany
Nephrocare Faro
🇵🇹
Faro, Portugal
Hospital de Santa Maria
🇵🇹
Lisboa, Portugal
Nephrocare Portimao
🇵🇹
Portimão, Portugal
St Georges Healthcare NHS Trust
🇬🇧
London, United Kingdom
Centre Hospitalier EpiCURA - Clinique Louis Caty de Baudour
🇧🇪
Baudour, Belgium
Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg
🇧🇪
Leuven, Belgium
CHR de la CITADELLE
🇧🇪
Liege, Belgium
KfH Nierenzentrum Coburg
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Coburg, Germany
Gemeinschaftspraxis und Dialysezentrum Karlstrass
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Düsseldorf, Germany
KfH Nierenzentrum Rosenheim
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Rosenheim, Germany
Hospital Universitario Reina Sofia
🇪🇸
Córdoba, Spain
Complejo Hospitalario de Torrecardenas
🇪🇸
Almeria, Spain
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
Hospital Clinic of Barcelona
🇪🇸
Barcelona, Spain
Servicio de Nefrologia Hospital General Universitario Gregorio Maranon
🇪🇸
Madrid, Spain
Hospital Galdakao-Usansolo
🇪🇸
Galdakao, Spain
Hospital 12 de Octubre
🇪🇸
Madrid, Spain
Cambridge University Hospitals NHS Trust
🇬🇧
Cambridge, United Kingdom
Hospital Universitario Puerta de Hierro Majadahonda
🇪🇸
Majadahonda, Madrid, Spain
Hospital Universitario Marques de Valdecilla
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Santander, Cantabria, Spain
Hospital de Torrevieja
🇪🇸
Torrevieja (Alicante), Spain
Glasgow Royal Infirmary
🇬🇧
Glasgow, United Kingdom