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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01999582

Enrollment

Registered

2013-12-03

Start date

2013-11-30

Completion date

2016-08-31

Last updated

2024-06-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anemia, Kidney Failure, Chronic

Keywords

Anemia, End Stage Kidney Disease, Chronic Kidney Disease, Dialysis, Erythrpoietin Stimulating Agent (ESA)

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.

Interventions

BIOLOGICALSotatercept

Sotatercept is dosed intravenously every 14 days. The dose a subject receives will depend on the randomization arm and the dose group.

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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.
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.
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

Measure	Time frame	Description
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).
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).

Countries

Belgium, Germany, Portugal, Spain, United Kingdom

Participant flow

Participants by arm

Arm	Count
Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) Injection Participants received sotatercept at 0.1 mg/kg administered IV every 14 days for up to 8 doses to evaluate the Pharmacokinetic (PK) and safety of IV versus subcutaneous (SQ) dosing of sotatercept.	7
Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) Injection Participants received sotatercept at 0.13 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.	7
Group 2: Sotatercept 0.2 mg/kg IV Injection Participants received sotatercept at 0.2 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.	9
Group 2: Sotatercept 0.26 mg/kg SC Injection Participants received sotatercept at 0.26 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.	9
Group 3: Sotatercept 0.1 - 0.4 mg/kg IV Injection Participants received sotatercept at a starting dose of 0.1 mg/kg. Intra subject dose escalation will be implemented in response to subjects' individual hemoglobin levels and can be increased in 0.1 mg/kg increments up to 0.4 mg/kg administered IV every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.	12
Group 3: Sotatercept 0.4 - 0.5 mg/kg SC Injection Participants received sotatercept at 0.4 mg/kg. Intra subject dose escalation will be implemented in response to subjects' individual hemoglobin levels and can be increased in 0.1 mg/kg increments up to 0.5 mg/kg administered SC every 14 days for up to 8 doses to evaluate the PK and safety of IV versus SC dosing of sotatercept.	6
Total	50

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Adverse Event	0	0	3	0	1	0
Overall Study	Lack of Efficacy	1	3	0	1	0	0
Overall Study	Other Reasons	1	0	3	1	1	2
Overall Study	Protocol Violation	1	0	0	0	0	1
Overall Study	Withdrawal by Subject	0	0	0	1	0	0

Baseline characteristics

Characteristic	Group 1: Sotatercept 0.13 mg/kg Subcutaneous (SC) Injection	Total	Group 3: Sotatercept 0.4 - 0.5 mg/kg SC Injection	Group 3: Sotatercept 0.1 - 0.4 mg/kg IV Injection	Group 1: Sotatercept 0.1 mg/kg Intravenous (IV) Injection	Group 2: Sotatercept 0.26 mg/kg SC Injection	Group 2: Sotatercept 0.2 mg/kg IV Injection
Age, Continuous	62.3 years STANDARD_DEVIATION 13.03	60.0 years STANDARD_DEVIATION 14.75	53.7 years STANDARD_DEVIATION 15.93	61.4 years STANDARD_DEVIATION 15.68	59.1 years STANDARD_DEVIATION 15.43	61.9 years STANDARD_DEVIATION 15.43	59.4 years STANDARD_DEVIATION 15.8
Ethnicity Hispanic or Latino	1 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Ethnicity Not Hispanic or Latino	6 Participants	48 Participants	6 Participants	12 Participants	7 Participants	9 Participants	8 Participants
Race American Indian/Alaska Native	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race Asian	0 Participants	5 Participants	0 Participants	0 Participants	2 Participants	1 Participants	2 Participants
Race Black or African- American	1 Participants	4 Participants	0 Participants	1 Participants	1 Participants	0 Participants	1 Participants
Race White	5 Participants	40 Participants	6 Participants	11 Participants	4 Participants	8 Participants	6 Participants
Sex: Female, Male Female	3 Participants	22 Participants	3 Participants	5 Participants	4 Participants	3 Participants	4 Participants
Sex: Female, Male Male	4 Participants	28 Participants	3 Participants	7 Participants	3 Participants	6 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 7	0 / 7	0 / 9	0 / 9	0 / 12	1 / 6
other Total, other adverse events	7 / 7	3 / 7	9 / 9	6 / 9	9 / 12	6 / 6
serious Total, serious adverse events	3 / 7	0 / 7	3 / 9	1 / 9	3 / 12	3 / 6

Outcome results

Primary

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.

Time frame: 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