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
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Celgene
- Enrollment
- 50
- Locations
- 46
- Primary Endpoint
- Estimate of Terminal Elimination Half-Life in Serum at Final Dose Only (t1/2)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
- •4. A Body Mass Index value ≥ 18.5 kg/m2 (kilograms per m2) at screening.
- •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
- •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.
Outcomes
Primary Outcomes
Estimate of Terminal Elimination Half-Life in Serum at Final Dose Only (t1/2)
Time Frame: 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)
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
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)
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
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
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
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)
Time Frame: 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)
Time Frame: 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)
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
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 Outcomes
- 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))
- 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 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))
- 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.)